bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–10–19
forty-four papers selected by
Grigor Varuzhanyan, UCLA
  1. Virtual screening and experimental validation of small-molecule compounds targeting AR in prostate cancer.
  2. Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.
  3. Ginsenoside Rh2 targets SIRT1-mediated deacetylation to modulate ERα/AR balance and overcome endocrine therapy resistance in prostate cancer using 3D organoid models.
  4. A Dual CYP17A1/HDAC6 Inhibitor for Targeted Prostate Cancer Therapy.
  5. Mechanistic Insights Into METTL1/WDR4-Mediated m7G Modification in Prostate Cancer Progression and Its Potential as a Therapeutic Target.
  6. Bone Metastatic Progression of Prostate Cancer is Regulated by TRIM28-LDHA Mediated Metabolism.
  7. HOXA13 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating SLC7A11 and SLC3A2.
  8. PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth.
  9. Circadian rhythm-related miR-6883-5p suppresses enzalutamide-resistant prostate cancer.
  10. Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival.
  11. Systematic characterization of cross-source miRNA biomarkers in prostate cancer with computational-experimental integrated analysis.
  12. The GR-LEDGF/p75-HSP27 Axis Contributes to Cross-Resistance Between Enzalutamide and Docetaxel in Prostate Cancer.
  13. Genomic and Transcriptomic Profiling of Radiation-Resistant, Locally Recurrent Prostate Cancer.
  14. MicroRNA-379 Modulates Prostate-Specific Antigen Expression Through Targeting the Androgen Receptor in Prostate Cancer.
  15. Re: Androgen Receptor Signaling Inhibitors in Non-Metastatic Castration-Resistant Prostate Cancer in Japan: The ARASHI Study.
  16. NDR1 enhances USP9X-mediated AR deubiquitination and promotes enzalutamide resistance in castration-resistant prostate cancer.
  17. Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth.
  18. Identification of key genes with differential correlations in prostate cancer.
  19. A smart gene circuit for precise regulation of tumor cell behavior.
  20. Innovative Se-Flutamide Derivatives: Enhanced Activity Toward Androgen Receptor (AR)-Dependent and -Independent Prostate Cancer Cells.
  21. Mistletoe Extracts Inhibit Progressive Growth of Prostate Cancer Cells.
  22. Nisin: The powerhouse metabolite of lactobacillus strains to defeat prostate cancer by targeting PCA3 lncRNA, apoptosis, and cell cycle pathways.
  23. Multifunctional nanoplatform as nano-inducer of ferroptosis for targeted recognition and imaging-guided therapy of metastatic prostate cancer.
  24. Fagonia cretica Inhibits Proliferation of Colorectal and Prostate Cancer Cells Through DNMT1 Downregulation, Oxidative Stress Induction, and ER-Beta Activation: An In Vitro and In Silico Study.
  25. The novel selective HDAC1 inhibitor ZJH-1 exhibits potent antitumor activity in castration-resistant prostate cancer, potentially involving HSP90AA1.
  26. Exploring the feasibility of PP1-docking motif-mimetic cell-penetrating peptides for modulating prostate carcinogenesis.
  27. Multi-layer stratified oncology platform utilizing transcriptomics, prostate cancer organoids, and modeling of drug response.
  28. Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate.
  29. In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance.
  30. Therapeutic Alliances for Optimizing the Management of Patients with Prostate Cancer: SOGUG Multidisciplinary Expert Panel Recommendations.
  31. The molecular aspects in prostatic cancer, unraveling the role of CDKs in prostate cancer progression.
  32. RCC2 and CD24 cooperate to modulate prostate cancer progression through vimentin ubiquitination and β-catenin activation.
  33. Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.
  34. Differences in prostate cancer treatment receipt and timeliness of treatment between African American/Black and White Iowans.
  35. Beyond Radiomics Alone: Enhancing Prostate Cancer Classification with ADC Ratio in a Multicenter Benchmarking Study.
  36. Biparametric magnetic resonance imaging-based radiomics model can improve the detection of dense and sparse prostate cancers.
  37. Preclinical Theranostic Profiling of [64Cu]Cu-Acetate in Prostate Cancer.
  38. Time and cost burden associated with docetaxel in patients with metastatic castration-sensitive prostate cancer initiating an androgen receptor pathway inhibitor-based regimen.
  39. Developing prognostic models for cholesterol-related genes linked with immune infiltration in prostate cancer.
  40. PEGylated liposomes co-encapsulating darolutamide and hesperetin for enhanced prostate cancer therapy: 2D, 3D PC3 models and in-vivo evaluation.
  41. Androgen receptors protect against thoracic aortic dissection via inhibiting ferroptosis of vascular smooth muscle cells in male patients.
  42. Periodontitis Promotes OSCC and Prostate Cancer Progression and Immunosuppression by Skewing Myeloid Differentiation of HSPCs.
  43. Evaluating the Clinical Competence of Large Language Models in Prostate Cancer Management: A Comparative Study of DeepSeek-R1 and ChatGPT.
  44. Prognostic Potential of Cancer-Associated Fibroblast Surface Markers and Their Specific DNA Methylation in Prostate Cancer.
  1. Mol Divers. 2025 Oct 16.
    Virtual screening and experimental validation of small-molecule compounds targeting AR in prostate cancer.
    Zhongqiang Fan, Xuexue Hao, Weiren Chen, Zhunan Xu, Qihua Wang, Muwei Li, Hao Zhang, Congzhe Ren, Yutong Chen, Jianping Lin, Xiaoqiang Liu.
      Prostate cancer ranks as the second most prevalent malignancy among men, with its progression predominantly driven by androgen receptor (AR) signaling. Despite the centrality of androgen deprivation therapy (ADT) in managing advanced prostate cancer, the emergence of resistance culminating in castration-resistant prostate cancer (CRPC) remains a formidable challenge. In this study, an integrative strategy for virtual screening was developed using a machine learning-based model implemented with Random Forest, followed by molecular docking. This strategy was employed to screen approximately 1,500,000 compounds, ultimately narrowing them down to 20 candidates. Among these, 8020-1599 and C301-6562 were identified as effective AR inhibitors. In vitro assays demonstrated that these compounds significantly inhibited the proliferation, migration, and invasion of prostate cancer cells, exhibiting efficacy comparable to that of the clinical standard, enzalutamide. In vivo experiments further validated their antitumor activity, demonstrating significant tumor growth inhibition without causing notable toxicity. Mechanistically, 8020-1599 and C301-6562 disrupted AR nuclear translocation and its downstream signaling pathways, leading to a marked reduction in the expression of AR-regulated genes FKBP5 and KLK3. This study highlights a promising approach for developing highly effective and minimally toxic AR inhibitors, although further research is required to assess their long-term safety and potential effects on alternative signaling pathways.
    Keywords:  Androgen receptor; Castration resistance; Prostate cancer; Small-molecule inhibitors; Virtual screening
    DOI:  https://doi.org/10.1007/s11030-025-11359-4
  2. Cancers (Basel). 2025 Sep 30. pii: 3187. [Epub ahead of print]17(19):
    Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.
    Pengfei Xu, Huan Qu, Joy C Yang, Fan Wei, Junwei Zhao, Menghuan Tang, Leyi Wang, Christopher Nip, Henson Li, Allen C Gao, Kit Lam, Marc Dall'Era, Yuanpei Li, Chengfei Liu.
       BACKGROUND: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood.
    METHODS: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine.
    RESULTS: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells.
    CONCLUSIONS: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.
    Keywords:  JAK/STAT; enzalutamide resistance; immune-related signaling; lineage plasticity; prostate cancer
    DOI:  https://doi.org/10.3390/cancers17193187
  3. Cell Biol Toxicol. 2025 Oct 15. 41(1): 139
    Ginsenoside Rh2 targets SIRT1-mediated deacetylation to modulate ERα/AR balance and overcome endocrine therapy resistance in prostate cancer using 3D organoid models.
    Xinan Chen, Wei Luo, Yueying Ren, Zezhong Mou, Chenyang Xu, Jimeng Hu, Mengbo Hu, Haowen Jiang.
      Resistance to endocrine therapy remains a major challenge in treating prostate cancer (PCa), highlighting the need for alternative therapeutic approaches. In this study, we investigated the potential of Ginsenoside Rh2 to counteract such resistance by influencing the SIRT1-dependent deacetylation pathway, thereby modulating the equilibrium between estrogen receptor α (ERα) and androgen receptor (AR). We proposed that Rh2 may suppress therapy-resistant PCa progression by adjusting ERα/AR transcriptional dynamics. Through network pharmacology analysis, key anti-PCa targets of Rh2 were identified, with Cytoscape enrichment indicating a pivotal role in AR signaling modulation. Functional validation was performed using 3D tumor organoids and human PCa cell lines (C4-2B and LNCaP) treated with Rh2 to assess cellular behaviors and receptor deacetylation status. Additionally, xenograft mouse models were employed to evaluate Rh2's in vivo effects, based on tumor burden, serum PSA levels, and tissue histopathology. Rh2 treatment led to significant, dose- and time-dependent inhibition of PCa cell proliferation and metastatic traits, accompanied by restored ERα/AR balance through activation of SIRT1. In animal studies, Rh2 notably reduced tumor size, decreased PSA expression, and improved systemic health indicators. Collectively, our results suggest that Rh2 re-sensitizes PCa to endocrine therapy by targeting the SIRT1 pathway, positioning it as a promising phytochemical candidate for managing resistant PCa. This work provides mechanistic insights supporting Rh2's potential for clinical translation.
    Keywords:  3D Organoid Model; ERα/AR Balance; Endocrine Resistance; Ginsenoside Rh2; Prostate Cancer; SIRT1 Deacetylation
    DOI:  https://doi.org/10.1007/s10565-025-10091-x
  4. FASEB J. 2025 Oct 31. 39(20): e71152
    A Dual CYP17A1/HDAC6 Inhibitor for Targeted Prostate Cancer Therapy.
    Hoang Yen Tran, Chien-Liang Lin, Hong-Yi Lin, Chih-Jie Shen, Ram Sharma, Jing-Ping Liou, Tsung-I Hsu.
      Prostate cancer remains a leading cause of cancer-related deaths in men, with androgen receptor (AR) signaling playing a critical role in disease progression. Although CYP17A1 inhibitors effectively suppress androgen biosynthesis, treatment resistance frequently emerges through alternative AR activation pathways. Additionally, histone deacetylase 6 (HDAC6) is implicated in AR hypersensitivity and stabilization, further contributing to castration-resistant prostate cancer. Thus, targeting both CYP17A1 and HDAC6 presents a promising therapeutic approach. We developed MPT1A160, a dual CYP17A1/HDAC6 inhibitor, and evaluated its efficacy on prostate cancer cells and a xenograft model. CCK-8 viability, wound healing, transwell migration, colony formation assays, and cell cycle analysis were performed. Immunoblotting quantified AR splice variant ARv7, AKR1C3, and KLK3 protein abundance, whereas Ki-67 and TUNEL staining assessed proliferation and apoptosis in tumor sections. Mice received DMSO, abiraterone, or MPT1A160 intraperitoneal injections twice per week. In silico analysis was used to assess oncogene expression and mutation frequencies in prostate cancer patient cohorts. MPT1A160 significantly suppressed prostate cancer cell viability with lower IC50 values and demonstrated superior tumor growth suppression in the 22Rv1 xenograft model compared to abiraterone. RNA-seq analysis revealed that MPT1A160 downregulated key oncogenic pathways and metabolic processes. Furthermore, several MPT1A160-suppressed genes exhibited high mutation frequencies in prostate cancer, suggesting their potential role in therapy resistance. MPT1A160 exhibits potent anti-tumor effects by targeting both androgen biosynthesis and epigenetic regulation, offering a novel dual inhibition strategy for overcoming treatment resistance in prostate cancer.
    Keywords:  AR signaling; chemoresistance; dual CYP17A1/HDAC6 inhibition; epigenetic regulation; prostate cancer
    DOI:  https://doi.org/10.1096/fj.202502614R
  5. J Biochem Mol Toxicol. 2025 Nov;39(11): e70546
    Mechanistic Insights Into METTL1/WDR4-Mediated m7G Modification in Prostate Cancer Progression and Its Potential as a Therapeutic Target.
    Wangdong Deng, Shanming Lu, Guodong Ding, Hanliang Zhu, Yiwen Chen, Yuantang Zhong, Zuomin Wang.
      N7-methylguanosine (m7G) represents a critical posttranscriptional modification linked to oncogenesis, but its involvement in prostate cancer (PCa) remains unclear. This study focuses on WD repeat domain 4 (WDR4) and methyltransferase like 1 (METTL1) to explore their function and therapeutic potential in PCa. Using qRT-PCR, Western blot, m7G RNA immunoprecipitation (MeRIP), and functional assays (CCK-8, Transwell, TUNEL), we investigated how METTL1/WDR4 regulate m7G modification, the PI3K/AKT/mTOR cascade, and target genes (MYC and VEGF), as well as their impact on DU145 cell growth, motility, invasion, and apoptosis. Both METTL1 and WDR4 were highly expressed in PCa samples and DU145 cells, correlated with elevated m7G tRNA modification levels. Their knockdown markedly inhibited DU145 cell growth, motility, and invasion, and facilitated apoptosis. These effects were associated with reduced m7G modification, suppression of the PI3K/AKT/mTOR pathway, and downregulation of MYC and VEGF expression, showing synergistic inhibitory effects. This study reveals that METTL1 and WDR4 are overexpressed in PCa and that, in DU145 cells, their knockdown was associated with suppressed m7G modification and attenuated oncogenic phenotypes. These model-specific findings suggest that METTL1/WDR4 may represent potential therapeutic targets in prostate cancer.
    Keywords:  METTL1; PI3K/AKT/mTOR signaling pathway; WDR4; m7G modification; prostate cancer
    DOI:  https://doi.org/10.1002/jbt.70546
  6. Mol Cancer Res. 2025 Oct 17.
    Bone Metastatic Progression of Prostate Cancer is Regulated by TRIM28-LDHA Mediated Metabolism.
    Miyeong Kim, Han Cong, Ryan Goettl, Jinpeng Liu, Ka-Wing Fong.
      Castration-resistant prostate cancer (CRPC), an advanced stage of prostate cancer (PCa), often leads to fatal bone metastasis. The vast majority of PCa patients who present with bone metastases suffer from bone lesions and other complications. Androgen receptor (AR) inhibitors, while improved, lack curative efficacy, necessitating an urgent demand for the development of innovative therapeutic strategies. TRIM28, also known as KAP1, is a transcription factor regulated by site-specific phosphorylation. Our recent study demonstrated that RSK1 is the protein kinase that directly phosphorylates TRIM28 at S473; as such, pS473-TRIM28 promotes the transcriptional activation of its gene targets. In this study, we reveal that TRIM28 S473 phosphorylation is readily detected in CRPC bone metastases, which is consistent with the previous report that RSK kinase is activated in PCa bone metastases. Using bioinformatic and genomic analysis, we uncovered that lactate dehydrogenase A (LDHA) is a novel TRIM28-induced gene in bone metastatic PCa. TRIM28 promotes the transcriptional activation of LDHA in a pS473-TRIM28 dependent manner. As such, TRIM28 is involved in LDH-related activities including lactate production and glycolysis. We also demonstrate that the TRIM28-LDHA axis is required for prostate tumor progression using an orthotopic bone injection model. Lastly, the application of an LDH inhibitor mitigates PCa development in bone. In summary, our study reveals an important role of the TRIM28-LDHA axis in PCa progression in bone, which may be targeted to mitigate the disease in the metastasis stage. Implications: TRIM28 upregulates LDHA and glycolysis, propelling prostate tumors in bone; pharmacologic LDH blockade mitigates disease.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-25-0676
  7. Cell Signal. 2025 Oct 12. pii: S0898-6568(25)00583-2. [Epub ahead of print] 112168
    HOXA13 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating SLC7A11 and SLC3A2.
    Yongliang Ma, Rui Liu, Pan Qi, Shufei Wei, Zongtao Ren, Aili Zhang, Bo Fan.
       BACKGROUND: HOXA13, a member of the homeobox gene family, has emerged as a potential oncogenic driver in prostate cancer (PCa). However, its regulatory role in ferroptosis and interactions with SLC7A11 and SLC3A2 remain unclear. This study investigates the functional significance of HOXA13 in PCa progression and its mechanistic link to SLC7A11/SLC3A2-mediated ferroptosis suppression.
    METHODS: HOXA13 expression in PCa tissues and cell lines was analyzed via RT-qPCR and Western blot. Functional assays (CCK-8, colony formation, wound healing, Transwell) and ferroptosis markers (ROS, MDA, iron levels) were evaluated in HOXA13-knockdown PCa cells. Transcriptional regulation of SLC7A11/SLC3A2 by HOXA13 was validated using ChIP-PCR, dual-luciferase reporter assays, and rescue experiments. In vivo tumor growth was assessed in nude mouse xenograft models. The positive signal of ki67, 4-HNE in tumor tissue was detected by immunohistochemical staining.
    RESULTS: HOXA13 was significantly upregulated in PCa tissues and cell lines compared to normal controls. HOXA13 knockdown elevated ROS, MDA, and intracellular iron levels, promoting ferroptosis, which was reversed by ferroptosis inhibitor (Ferrostatin-1). Knockdown HOXA13 inhibited PCa cell proliferation, migration, and invasion, partially rescued by SLC7A11/SLC3A2 overexpression. HOXA13 directly bound to promoters of SLC7A11 and SLC3A2, enhancing their transcription. SLC7A11/SLC3A2 reversed ferroptosis and restored tumor growth in vitro and in vivo. HOXA13 knockdown suppressed xenograft tumor growth in mice, while SLC7A11/SLC3A2 overexpression restored tumorigenicity.
    CONCLUSION: HOXA13 drives PCa progression by transcriptionally activating SLC7A11 and SLC3A2, which suppress ferroptosis and enhance proliferation and metastasis. The findings highlighted sh-HOXA13 promoting ferroptosis as a potential strategy for PCa treatment.
    Keywords:  Ferroptosis; HOXA13; Prostate cancer; SLC7A11/SLC3A2
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112168
  8. Cancer Res. 2025 Oct 17.
    PRDM16 Regulates Prostate Cancer Cell Dormancy and Prevents Bone Metastatic Outgrowth.
    Mostafa M Nasr, Bishoy Wadie, Tao Li, Jeremy S Frieling, Haley du Bois, Ryan T Bishop, Marilena Tauro, Baasil Malik, Karl J Nyman, Conor C Lynch.
      Understanding dormancy in prostate cancer (PCa) is challenging due to model availability. Here, using murine and human PCa cell lines, we generated a stress-induced model of dormancy in vitro and demonstrated that the phenotype could be sustained upon intrailiac artery delivery into the bone marrow microenvironment. RNA-Seq analysis revealed that the transcription factor PR domain containing 16 (PRDM16) was commonly upregulated in dormant PCa cells compared to controls. Further, bone marrow disseminated tumor PCa cells from primary orthotopic tumors were largely positive for PRDM16. Genetic ablation and forced ectopic expression supported a role for PRDM16 in maintaining PCa dormancy in vitro and in vivo. Clinically, PRDM16 negatively correlated with disease recurrence, and PRDM16 negatively correlated with the E2F cell cycle program in disseminated tumor cells derived from PCa patient bone marrow. Gene enrichment and characterization studies implicated PRDM16 as a regulator of metabolic and cell cycle pathways. ChIP-qPCR further revealed that PRDM16 binds upstream of the promoter of RB1, a potent repressor of E2F activity. Overall, this study developed a straightforward method for inducing cancer cell dormancy and applied this approach to find that PRDM16 governs an intrinsic dormancy program in PCa.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4809
  9. Noncoding RNA Res. 2026 Feb;16 21-31
    Circadian rhythm-related miR-6883-5p suppresses enzalutamide-resistant prostate cancer.
    Wenchang Yue, Chao Li, Tao Wang, Jiawei You, Jiale Sun, Jiapeng Liu, Ashutosh K Tewari, Kyprianou Natasha, Mariana G Figueiro, Jianquan Hou, Babu J Padanilam.
      The increasing incidence of prostate cancer (PCa), particularly the emergence of treatment-resistant castration-resistant prostate cancer (CRPC), has intensified research efforts to address this lethal disease. Circadian rhythm gene alterations have been identified as critical factors influencing PCa progression and treatment resistance, warranting further investigation into their roles in PCa biology. In this study, we identified a significant downregulation of PER1 and its associated miRNA, miR-6883-5p, in PCa cells and clinical samples, suggesting their potential clinical relevance. Functional analyses demonstrated that miR-6883-5p suppresses the proliferation of enzalutamide-resistant PCa cells both in vitro and in vivo by directly targeting AR-V7. Furthermore, we delineated the regulatory functions of the transcription factors BMAL1 and CLOCK in promoting the expression of PER1 and miR-6883-5p, while miR-6883-5p negatively regulates CLOCK expression, thereby impacting the transcription-translation feedback loop (TTFL) of circadian genes. Collectively, these findings uncover a regulatory axis involving circadian rhythm components, miR-6883-5p, AR-V7, and PCa progression, providing new mechanistic insights into treatment resistance in CRPC and highlighting the circadian clock as a potential therapeutic target.
    Keywords:  AR-V7; Circadian rhythm; Enzalutamide resistance; MicroRNA; PER1; Prostate cancer
    DOI:  https://doi.org/10.1016/j.ncrna.2025.09.002
  10. Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2509222122
    Protein disulfide isomerases regulate androgen receptor stability and promote prostate cancer cell growth and survival.
    Jianling Xie, Kaikai Shen, Wenken Liang, Zijian Kuang, Raj K Shrestha, Adrienne R Hanson, Scott L Townley, Meiling He, Sishu Yu, Peiwen Zhou, Liangzhen Zhu, Zhiwen Gong, Xiang Ao, Sushma R Rao, Qing Zhang, Kaijie Chen, Jinfen Wei, Shashikanth Marri, Marten F Snel, Swati Irani, Liye Chen, Ling Wang, Daniel P McDougal, John B Bruning, Minglin Ou, Shaobo Wang, Christopher G Proud, Hongli Du, Lisa M Butler, Luke A Selth.
      Cancer cells exhibit accelerated protein production to accommodate their high rates of growth and proliferation. Elevated protein synthesis creates a dependency on endoplasmic reticulum (ER)-resident proteins and chaperones, which are required to maintain proteostasis. In this study, we identified the protein disulfide isomerases (PDIs) PDIA1 and PDIA5, which play a critical role in folding of client proteins in the ER, as important regulators of prostate cancer growth and response to therapy. PDIA1 and PDIA5 are upregulated in prostate cancer and induced by the androgen receptor (AR) signaling axis. Genetic or pharmacological disabling of PDIA1/PDIA5 caused redox stress, mitochondrial dysfunction, growth inhibition, and death of prostate cancer cells in vitro and in vivo. The critical functions of these enzymes in redox homeostasis and cell survival were observed in both AR-driven and AR-independent models of prostate cancer. Loss of PDIA1/PDIA5 activity led to ubiquitination and degradation of the AR, revealing a feedback loop between these chaperones and the AR pathway. Mechanistically, PDIA1/PDIA5 regulated AR stability by mediating disulfide bond formation, an activity that required cysteines 669 and 844 in AR's ligand-binding domain. Importantly, targeting PDIAs sensitized prostate cancer cells to the AR antagonist, enzalutamide. This study reveals a mechanism governing AR proteostasis in prostate cancer and positions PDIA1/5 as viable therapeutic targets.
    Keywords:  PDIA1; PDIA5; androgen receptor; prostate cancer; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2509222122
  11. Front Cell Dev Biol. 2025 ;13 1605297
    Systematic characterization of cross-source miRNA biomarkers in prostate cancer with computational-experimental integrated analysis.
    Huimin Lu, Wenjin Li, Zhongxin Huang, Libo Chen, Mingyong Li, Weiming Deng.
       Purpose: Prostate cancer (PCa) is occult and remains largely incurable once it metastasizes. Our research aims to identify the key miRNAs and construct miRNA-mRNA networks for PCa.
    Methods: The microarray dataset GSE112264, consisting of 1,591 male serum samples, and tissue miRNA data from TCGA, including 497 prostate cancer and 52 normal samples, were included in the analysis. Differentially expressed miRNAs (DE-miRNAs) were detected, and miRTarBase was used to predict the common target genes. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the target genes. The protein-protein interaction (PPI) network, which revealed the top 10 hub genes, was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. The expression of the potential hub genes was examined using the UALCAN database. Finally, GSE112264, TCGA datasets, and clinical samples were used to verify the consistency of miRNA expressions in serum and tissue.
    Results: A total of 948 target genes of the two overlapped downregulated miRNAs (miR-146a-3p and miR-136-3p) were predicted. Functional enrichment analysis indicated that significant DE-miRNAs were related to PCa-related pathways, such as protein binding, the mammalian target of rapamycin (mTOR) signaling pathway, and porphyrin and chlorophyll metabolisms. Four hub genes were identified from the PPI network, namely, NSF, HIST2H2BE, IGF2R, and CADM1, and verified to be aberrantly expressed in the UALCAN database. Experiment results indicated that only miR-136-3p was markedly reduced in both serum and tissue.
    Conclusion: In this study, we established the miRNA-mRNA network, offering potential PCa targets.
    Keywords:  bioinformatics; biomarkers; microRNA; prostate cancer; regulatory network
    DOI:  https://doi.org/10.3389/fcell.2025.1605297
  12. Cells. 2025 Oct 09. pii: 1566. [Epub ahead of print]14(19):
    The GR-LEDGF/p75-HSP27 Axis Contributes to Cross-Resistance Between Enzalutamide and Docetaxel in Prostate Cancer.
    Pedro T Ochoa, Evelyn S Sanchez-Hernandez, Alfonso M Duran, Kai Wen Cheng, Joel Philip, Tise Suzuki, Julia J Unternaehrer, Julie Dutil, Bhaskar Das, Rituparna Ganguly, Yasmine Baca, David de Semir, Charles Wang, Isaac Kremsky, Carlos A Casiano.
      An emerging challenge in prostate cancer (PCa) treatment is the development of drug cross-resistance, wherein resistance to enzalutamide (ENZ), an androgen receptor signaling inhibitor (ARSI), also confers resistance to subsequent ARSI and docetaxel (DTX) treatments. The mechanisms underlying this drug cross-resistance remain unclear. Through RNA sequencing, we identified 93 overlapping differentially expressed genes (DEGs) in ENZ- and DTX-resistant PCa cells. Among the DEGs, HSPB1, which encodes heat shock protein 27 (HSP27), emerged as a key gene of interest. HSP27 is a known target of lens epithelium-derived growth factor p75 (LEDGF/p75), a transcription coactivator regulated by glucocorticoid receptor (GR). Both GR and LEDGF/p75 are overexpressed in advanced PCa and promote drug resistance. HSP27 was overexpressed in ENZ and DTX cross-resistant PCa cell lines and its expression was decreased upon GR or LEDGF/p75 silencing. ChIP sequencing confirmed GR binding at the HSPB1 promoter. Pharmacological targeting of HSP27 in drug-resistant cells reduced proliferation, clonogenicity, and tumorsphere formation, and restored sensitivity to ENZ and DTX. Notably, high transcript expression of a GR-LEDGF/p75-HSP27 gene panel correlated with worse overall survival in PCa patients (n = 4259). These findings identified this axis as a driver of PCa drug cross-resistance and promising therapeutic target for overcoming treatment failure.
    Keywords:  HSP27; LEDGF/p75; RNA sequencing; docetaxel; drug cross-resistance; enzalutamide; glucocorticoid receptor; prostate cancer
    DOI:  https://doi.org/10.3390/cells14191566
  13. Int J Radiat Oncol Biol Phys. 2025 Sep 29. pii: S0360-3016(25)06298-4. [Epub ahead of print]
    Genomic and Transcriptomic Profiling of Radiation-Resistant, Locally Recurrent Prostate Cancer.
    Beth K Neilsen, Rong Rong Huang, Luca F Valle, James A Proudfoot, Elai Davicioni, Liying Zhang, Una Ryg, Melanie Schulz-Jaavall, Joanne B Weidhaas, Milisuryani Santoso, Sophia Parmisano, Jeremie Calais, Robert E Reiter, Matthew B Rettig, Michael L Steinberg, Anthony Sisk, Wayne Brisbane, Leonard S Marks, Paul C Boutros, Wolfgang H Lilleby, Amar U Kishan.
       PURPOSE: The biology of locally radiorecurrent prostate cancer (LRR-PCa) is poorly understood.
    METHODS AND MATERIALS: We sought to explore the genomic and transcriptomic landscape of LRR-PCa with targeted DNA sequencing and RNA expression analysis from 41 biopsy-proven LRR-PCa tumors from 36 unique patients who had a recurrence at a median interval of 84 months (IQR, 70-124 months). Genomic alteration frequencies and transcriptomic data were compared between the LRR-PCa cohort and treatment-naïve patients from the Cancer Genome Atlas (genomic; n = 496) and Gleason grade-at-recurrence-matched patients from the Decipher Genomics Resource for Intelligent Discovery (transcriptomic; n = 22,320).
    RESULTS: Twenty-five patients (69%) had pathologic upgrading at recurrence (17% vs 64% with Gleason grade 4-5 disease; P < .001). The LRR-PCa cohort demonstrated significantly greater single-nucleotide variations in 29 genes known to be associated with prostate cancer, including several associated with increased aggressiveness and DNA repair: FAT1 (58.5% vs 1.0%), RAD51B (36.6% vs 0.4%), POLQ (34.1% vs 1.4%), KMT2C (34.1% vs 4.9%), BRCA2 (29.3% vs 1.8%), ATRX (26.8% vs 0.8%), and BRCA1 (24.4% vs 0.4%) (Pvalues < .001 for all). The LRR-PCa cohort had a significantly higher Decipher score (median, 0.80 vs 0.66; P = .05) and demonstrated significantly greater basal subtype based on PAM50 (56% vs 20%; P < .001) and lower androgen receptor activity (61% for LRR vs 9%; P < .001).
    CONCLUSIONS: Overall, these results suggest that LRR-PCa has a distinct genomic and transcriptomic landscape from de novo prostate cancer. Specifically, LRR-PCa has an enrichment in SNVs in genes associated with tumor aggressiveness and/or DNA repair, has higher Decipher scores, a more basal subtype, and has transcriptomic evidence of lower androgen receptor activity and loss of tumor suppressor genes.
    DOI:  https://doi.org/10.1016/j.ijrobp.2025.09.035
  14. Cancers (Basel). 2025 Oct 07. pii: 3245. [Epub ahead of print]17(19):
    MicroRNA-379 Modulates Prostate-Specific Antigen Expression Through Targeting the Androgen Receptor in Prostate Cancer.
    James R Cassidy, Margareta Persson, Gjendine Voss, Kira Rosenkilde Underbjerg, Tina Catela Ivkovic, Anders Bjartell, Anders Edsjö, Hans Lilja, Yvonne Ceder.
      Background: MicroRNA-379 (miR-379) has been reported to play a tumour-suppressing role in several cancer types. Our previous work demonstrated that miR-379 overexpression attenuates the metastatic spread of prostate cancer (PCa) both in vitro and in vivo. However, the underlying mechanisms remain poorly understood. Methods: To elucidate the mechanisms by which miR-379 affects metastases, we performed a cytokine array to identify secreted proteins modulated by miR-379 dysregulation in a bone microenvironment model. We then assessed the levels of the key candidate, and performed functional studies, including reporter assays, of the transcriptional regulation. Results: Prostate-specific antigen (PSA)-the clinically widely used blood biomarker for PCa-emerged as the most significantly affected secreted protein. We observed that PSA secretion increased following miR-379 inhibition and decreased with miR-379 overexpression, with parallel changes in intracellular PSA levels. However, our data suggests that miR-379 does not directly regulate PSA expression. Instead, miR-379 appears to downregulate androgen receptor (AR) expression by targeting its 3'-untranslated region (3'-UTR), thereby indirectly reducing PSA transcription through diminished AR-mediated promoter activation. Supporting this indirect mechanism, analysis of clinical samples from prostate cancer patients revealed an inverse correlation between expression of miR-379 in prostatic tissue and serum PSA levels. Furthermore, reduced miR-379 expression was associated with increased levels of AR immunostaining in malignant tissues. Conclusions: Taken together, these findings suggest that miR-379 negatively regulates PSA secretion indirectly via suppression of AR, and that the interplay between miR-379, AR, and PSA may contribute to the metastatic progression of PCa to bone.
    Keywords:  metastases; microRNA; oncogenic and tumor-suppressive miRNAs; prostate cancer
    DOI:  https://doi.org/10.3390/cancers17193245
  15. Int J Urol. 2025 Oct 15.
    Re: Androgen Receptor Signaling Inhibitors in Non-Metastatic Castration-Resistant Prostate Cancer in Japan: The ARASHI Study.
    Takashi Kawahara.
      
    DOI:  https://doi.org/10.1111/iju.70259
  16. Int J Biol Sci. 2025 ;21(13): 5628-5644
    NDR1 enhances USP9X-mediated AR deubiquitination and promotes enzalutamide resistance in castration-resistant prostate cancer.
    Zeyuan Zheng, Jinxin Li, Yifan Du, Liyan Li, Qingqing Wu, Bin Liu, Haodong Wu, Zeyi Zhang, Zuodong Xuan, Yue Zhao, Huimin Sun, Chen Shao.
      Castration-resistant prostate cancer (CRPC) enzalutamide resistance is a significant issue in the current treatment of prostate cancer (PCa). Previously, nuclear Dbf2-related 1 (NDR1) was found to influence metastasis in PCa patients; however, the role of NDR1 in enzalutamide resistance in CRPC remains unclear. In this study, we found that after CRPC cells developed resistance to enzalutamide, NDR1 expression levels were elevated and that NDR1 expression could reduce the sensitivity of CRPC cells to enzalutamide. Furthermore, in androgen receptor (AR) positive PCa cell lines, the use of enzalutamide induced an increase in NDR1 expression levels. Further mechanistic exploration revealed that NDR1 positively regulates AR protein expression levels by promoting the deubiquitination of AR by USP9X, thereby increasing AR stability, which leads to cellular resistance to enzalutamide. Finally, we confirmed that pharmacological suppression of NDR1 by 17AAG significantly inhibited the growth of enzalutamide-resistant CRPC tumors in both in vitro and in vivo models. In summary, this study revealed that NDR1 enhances the deubiquitination of AR mediated by USP9X, improving its stability and activity and thereby maintaining the continuous activation of the androgen signaling pathway in CRPC, leading to resistance to enzalutamide treatment. These findings suggest that cotargeting NDR1 and AR may represent a novel therapeutic strategy for AR-positive CRPC.
    Keywords:  AR; Castration-resistant prostate cancer; Enzalutamide resistance; NDR1; USP9X
    DOI:  https://doi.org/10.7150/ijbs.114686
  17. Mol Cancer. 2025 Oct 14. 24(1): 256
    Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth.
    Aleksandra Fesiuk, Daniel Pölöske, Elvin D de Araujo, Geordon A Frere, Timothy B Wright, Gary Tin, Yasir S Raouf, Olasunkanmi O Olaoye, Ji Sung Park, Nicolas Blavet, Boris Tichý, Michaela Schlederer, Sandra Högler, Michael Wolf, Cécile Philippe, Osman Aksoy, Adam Varady, Alejandro Medaglia Mata, Maxim Varenicja, Boglárka Szabó, Theresa Weiss, Gabriel Wasinger, Torben Redmer, Heidi A Neubauer, Martin Susani, Clemens P Spielvogel, Jing Ning, Maik Dahlhoff, Martin Schepelmann, Richard Kennedy, Richard Moriggl, Geoffrey Brown, Jenny Persson, Christopher Gerner, Vojtech Bystry, Oldamur Hollóczki, David M Heery, Patrick T Gunning, Olaf Merkel, Brigitte Hantusch, Lukas Kenner.
      Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein µ-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor β (TRβ), which is the main effector of TH signaling, in the context of PCa. The use of the TRβ-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models in vivo. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide, and their combined use was synergistic. Evidence from human datasets corroborates our findings, whereby elevated TRβ expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TRβ as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.
    Keywords:  Androgen receptor; Murine PCa model; NH-3; Prostate cancer; Thyroid hormone receptor β
    DOI:  https://doi.org/10.1186/s12943-025-02451-2
  18. Aging (Albany NY). 2025 Oct 10. 17
    Identification of key genes with differential correlations in prostate cancer.
    Zepai Chi, Yuanfeng Zhang, Xuwei Hong, Tenghao Yang, Qingchun Xu, Weiqiang Lin, Yueying Huang, Yonghai Zhang.
       BACKGROUND: Prostate cancer, a major global health issue for men, remains a critical clinical challenge in treatment, highlighting the need for improved biomarkers. Treatment options for prostate cancer include active surveillance, surgery, endocrine therapy, chemotherapy, radiotherapy, immunotherapy, etc. However, as the tumor progresses, the effectiveness of treatment regimens gradually decreases. Therefore, we need to understand the biological mechanisms that promote prostate cancer tumorigenesis and progression and to screen biomarkers for diagnosis and prediction of prognosis.
    METHODS: We utilized the expression profiles of prostate cancer from The Cancer Genome Atlas (TCGA) database and employed weighted gene co-expression network analysis (WGCNA) to construct a gene interaction network. Gene co-expression networks were constructed using WGCNA (soft-threshold power β = 10, scale-free R² > 0.9), with differential correlations computed via Fisher's z-test (FDR < 0.05). We used the "DiffCorr" package to discriminate between tumor and adjacent normal tissues to identify genes with differential representation in tumor and normal tissues, and perform in-depth analysis of these genes.
    RESULTS: Through WGCNA analysis, we identified a total of 20 modules, three gene modules were significantly associated with prostate cancer. We then analyzed the genes in these modules separately by the "DiffCorr" package and intersected these with differentially expressed genes. Finally, 21 genes were screened as biomarkers for prostate cancer.
    CONCLUSIONS: Our study unveils a prostate cancer tumorigenesis mechanism by identifying differentially correlated gene pairs during normal-to-tumor transformation. We believe that the biomarkers derived from this algorithm have important reference implications for future research in prostate cancer.
    Keywords:  DiffCorr; TCGA; WGCNA; biomarkers; prostate cancer
    DOI:  https://doi.org/10.18632/aging.206323
  19. Synth Syst Biotechnol. 2026 Mar;11 237-246
    A smart gene circuit for precise regulation of tumor cell behavior.
    Hao Fu, Zhiwei Zhou, Lan Fang, Qing Wang, Xin Tang, Wei Su, Xuancai Chen, Yachun Tang, Qun Zhou.
      Personalized gene circuit is a robust mode of cellular regulation that can manipulate intracellular gene expression to achieve desired functional regulation. However, the construction of logic circuits that automatically sense the characteristics of a particular environment within a cell is often difficult and lacking in sensitivity. Here, we synthesize from scratch specific promoters capable of sensing in cells, and use the combination of different types of promoters to construct smart gene circuits that can regulate gene expression in specific cell types sensitively. In detail, the tumour-specific promoter and the prostate tissue-specific promoter were constructed to be combined together into generating an artificial AND-gate gene circuit using the CRISPR-Cas9 system which could identify prostate cancer selectively. We then utilized this artificial gene circuit to drive targeted genes expression, such as P21, E-cadherin and Bax, to inhibit multifunctional prostate cancer cells but not other cells. Moreover, we applied gene circuits to redirect endogenous genes within cells and significantly and specifically suppressed the tumor growth of prostate cancer in vivo. Overall, these results highlight the clinical potential of these gene circuits as specific tools for prostate cancer detection and treatment, which is a new method for specifically reprogramming prostate cancer cells in vivo and may serve as a promising treatment strategy.
    Keywords:  CRISPR-System; Gene circuit; Gene regulation; Promoter; Prostate cancer
    DOI:  https://doi.org/10.1016/j.synbio.2025.09.016
  20. Arch Pharm (Weinheim). 2025 Oct;358(10): e70119
    Innovative Se-Flutamide Derivatives: Enhanced Activity Toward Androgen Receptor (AR)-Dependent and -Independent Prostate Cancer Cells.
    Cristina Morán-Serradilla, Carmen Sanmartín, Asif Raza, Ignacio Encío, Daniel Plano, Arun K Sharma.
      Sixteen novel selenoderivatives of flutamide, which is used for treating androgen receptor (AR)-dependent prostate cancer, were developed. All the Se derivatives displayed promising activity against the NCI-60 human cancer cell line panel, which also includes two AR-independent prostate cancer cell lines, DU-145 and PC-3. Conversely to flutamide, compounds a2, a5, and b4 exhibited a potent antiproliferative effect toward AR-dependent LNCaP cells. Several cell death inhibitors were used to determine the underlying regulated cell death processes of a5. Regarding its mechanism of action in these cells, this compound promoted apoptosis by activating both intrinsic and extrinsic apoptotic pathways, without generating reactive oxygen species (ROS). Besides, it induced the G0/G1 cell cycle arrest. Altogether, it could be concluded that this Se-flutamide analog could be a feasible and promising candidate for further development for the treatment of both AR-dependent and -independent prostate cancers.
    Keywords:  flutamide; prostate cancer; selenium
    DOI:  https://doi.org/10.1002/ardp.70119
  21. Cells. 2025 Sep 30. pii: 1535. [Epub ahead of print]14(19):
    Mistletoe Extracts Inhibit Progressive Growth of Prostate Cancer Cells.
    Sascha D Markowitsch, Larissa Albrecht, Moritz Meiborg, Jochen Rutz, Anita Thomas, Felix K-H Chun, Axel Haferkamp, Eva Juengel, Roman A Blaheta.
      Although multimodal therapeutic management has significantly improved outcome in prostate cancer (PCa) patients, treatment options for castrate-resistant disease remain challenging. Plant-derived mistletoe extracts have supported cancer patients and are, therefore, widely used as complementary medicine. However, mechanisms behind possible mistletoe benefits to PCa patients remain to be explored. The present study was designed to evaluate the effect of mistletoe extracts from four different host trees (Tiliae, Populi, Salicis, and Crataegi) on the growth and proliferation of PCa cell lines in vitro. PC3, DU145, and LNCaP cells were used to evaluate tumor cell growth (MTT assay) and proliferation (BrdU incorporation assay). Clonogenicity, apoptosis, cell cycle, and cell-cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins) were investigated, as was CD44 standard and splice variant expression and integrin α and β receptors. SiRNA knockdown studies were employed to investigate the functional relevance of integrins. All mistletoe extracts significantly inhibited cell growth in a dose-dependent manner and cell proliferation and clonogenicity were suppressed. Populi and Salicis induced cell-cycle arrest in the G2/M phase and increased apoptosis. Both extracts down-regulated CDK1 and cyclin A and altered CD44 expression. Integrins α5 in all cell lines and α6 in DU145 and LNCaP were particularly diminished. Knocking down α5 and α6 induced cell growth inhibition in DU145. Mistletoe extracts block the growth and proliferation of PCa cells in vitro and therefore qualify for use in future animal studies to evaluate mistletoe as an adjunct to standard PCa treatment.
    Keywords:  cell cycling; growth; mistletoe; proliferation; prostate cancer
    DOI:  https://doi.org/10.3390/cells14191535
  22. Folia Microbiol (Praha). 2025 Oct 17.
    Nisin: The powerhouse metabolite of lactobacillus strains to defeat prostate cancer by targeting PCA3 lncRNA, apoptosis, and cell cycle pathways.
    Runheng Zhao, Wenfang Liu, Ke Wang, Hongxia Li, Haiyuan Li.
      Prostate cancer remains a major global health challenge, driving the need for innovative therapies. Nisin, an antimicrobial peptide from Lactobacillus lactis, has shown anticancer effects in various malignancies, yet its impact on prostate cancer and the prostate cancer antigen 3 (PCA3) long non-coding RNA (lncRNA) remains unstudied. This research aimed to investigate nisin's anticancer properties in prostate cancer cells, focusing on PCA3 lncRNA, apoptosis, and cell cycle pathways. Human prostate adenocarcinoma (LNCaP) and normal human foreskin fibroblast (HFF2) cells were treated with nisin. Cell viability was measured using MTT assays, while apoptosis and cell cycle progression were assessed via flow cytometry. Quantitative PCR (qPCR) evaluated gene expression of PCA3 lncRNA, apoptosis-related genes, cell cycle regulators, and PCA3-associated microRNAs and mRNAs. In-silico analysis of TCGA-PRAD data explored PCA3's regulatory network. Nisin selectively reduced LNCaP cell viability (IC₅₀: 370.7 μM at 24 h, 177.2 μM at 48 h) compared to HFF2 cells (IC₅₀: 887.8 μM at 24 h, 406.5 μM at 48 h). It induced time-dependent apoptosis and G1 phase cell cycle arrest in LNCaP cells. Nisin downregulated PCA3 lncRNA expression, upregulated miR-132-3p and miR-1261, and altered SREBP1 and PRKD3 gene expression, modulating the PCA3 regulatory network. This study is the first to explore nisin's anticancer effects in prostate cancer, uniquely targeting PCA3 lncRNA and its downstream regulatory pathways. Nisin demonstrates potent anticancer effects in prostate cancer cells by inducing apoptosis, arresting cell cycle progression, and modulating the PCA3 lncRNA network, suggesting its potential as a novel therapeutic agent.
    Keywords:  Apoptosis; Cell cycle; Lactobacillus; Nisin; PCA3 lncRNA; Prostate cancer
    DOI:  https://doi.org/10.1007/s12223-025-01362-5
  23. Mater Today Bio. 2025 Dec;35 102317
    Multifunctional nanoplatform as nano-inducer of ferroptosis for targeted recognition and imaging-guided therapy of metastatic prostate cancer.
    Liang He, Hao Liang, Jixue Wang, Annan Liu, Lei Li, Ji Lu, Ze Wang, Andrew K Whittaker, Quan Lin.
      Metastasis prostate cancer (PCa) precision detection and effective treatment remain significant challenge in clinic. Ferroptosis brought promising therapeutic strategy for the treatment of metastatic PCa, effectively inducing ferroptosis in PCa cells represents key to improve therapeutic efficacy. Herein, we developed a multifunctional nanoplatform Fe/Au nanodots-bombesin (FGN-BBN) as the ferroptosis nano-inducer to generate large amount of ROS to induce ferroptosis through an "open-source throttling" strategy for targeted imaging-guided therapy of metastatic PCa. On the one hand, FGN-BBN serves as an efficient biomimetic nanozyme and photothermal agent, exhibiting great POD-like activity and generating abundant reactive oxygen species (ROS) via photothermal-enhanced chemodynamic therapy (CDT) to induce ferroptosis, which is achieving "open source" aspect. On the other hand, FGN-BBN exhibit GPx-like activity that depletes overexpressed glutathione (GSH) within the tumor microenvironment, thereby preventing the neutralization of ROS and achieving the "throttling" effect. Furthermore, bombesin facilitates targeted delivery of the nanozyme to metastatic PCa cells, synergistically enhancing ferroptosis activity. In terms of diagnosis, FGN-BBN possesses targeted recognition capabilities and enables multimode bioimaging including fluorescence (FL), computed tomography (CT), and magnetic resonance imaging (MRI), allowing for the "visualization" of tumor localization and real-time imaging-guided therapy. In summary, the multifunctional nanoplatform integrates multienzyme activity, targeted recognition, multimodal imaging, photothermal therapy, and CDT to induce high-efficiency ferroptosis, offering an effective theranostic strategy for metastatic PCa.
    Keywords:  Ferroptosis nano-inducer; Metastasis prostate cancer; Multi-mode imaging; Nanozyme; Tumor targeting
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102317
  24. J Ethnopharmacol. 2025 Oct 14. pii: S0378-8741(25)01433-3. [Epub ahead of print] 120741
    Fagonia cretica Inhibits Proliferation of Colorectal and Prostate Cancer Cells Through DNMT1 Downregulation, Oxidative Stress Induction, and ER-Beta Activation: An In Vitro and In Silico Study.
    Apurva Kirti, Manisha Tiwari.
       ETHNOPHARMACOLOGICAL RELEVANCE: Fagonia cretica L. is a traditionally used medicinal plant in many cultures for the management of cancer and other ailments. However, systematic scientific evaluation of its anticancer efficacy and mechanisms remains limited.
    AIM OF THE STUDY: To investigate the antiproliferative effects and underlying molecular mechanisms of an ethanolic extract of Fagonia cretica against colorectal (HCT-116) and prostate (PC3) cancer cell lines.
    MATERIALS AND METHODS: The cytotoxic potential of F. cretica ethanolic extract was assessed by in vitro cell viability assays. Bioinformatics analyses and experimental validation were used to identify molecular targets and cellular pathways affected by the extract.
    RESULTS: The F. cretica extract exhibited potent antiproliferative activity in both colorectal and prostate cancer cell lines. Integrated in silico and experimental studies identified DNA methyltransferase 1 (DNMT1) as a principal molecular target of the plant's phytoconstituents. Treatment with the extract led to significant downregulation of DNMT1 at both protein and mRNA levels, accompanied by promotion of apoptosis and induction of oxidative stress. Furthermore, a marked upregulation of the tumor suppressor gene ER-β was observed following extract exposure. These dual actions, suppression of DNMT1 and activation of ER-β, appear central to the mechanism underlying the anticancer effects of F. cretica.
    CONCLUSION: Our study provides scientific validation for the ethnomedicinal use of Fagonia cretica as an anticancer agent. By targeting both epigenetic and apoptotic pathways, this plant extract offers promise as a natural therapeutic candidate for colorectal and prostate cancer management. Further studies are warranted to isolate active constituents and evaluate efficacy in vivo.
    Keywords:  Anticancer; Colorectal; DNMT1; Fagonia cretica; Natural extract; Prostate
    DOI:  https://doi.org/10.1016/j.jep.2025.120741
  25. Chem Biol Interact. 2025 Oct 10. pii: S0009-2797(25)00407-7. [Epub ahead of print]421 111777
    The novel selective HDAC1 inhibitor ZJH-1 exhibits potent antitumor activity in castration-resistant prostate cancer, potentially involving HSP90AA1.
    Yizhong Bao, Jitao Li, Aokang Zhang, Yixiu Ni, Mingjing Bi, Jun Chen.
      Histone deacetylase (HDAC) inhibitors are being explored as a therapeutic approach for prostate cancer (PCa), particularly castration-resistant variants with limited treatment options. In this study, we designed and synthesized ZJH-1, a novel hydroxamate-based HDAC1-selective inhibitor, and systematically evaluated its anti-tumor efficacy and molecular mechanisms. Biochemical and affinity analyses showed ZJH-1 possesses the highest HDAC1 selectivity among isoforms, associated with H3 hyperacetylation at Lys9/27 in PCa cells. ZJH-1 demonstrated cytotoxic effects (IC50 = 65 nM in PC3 cells and 345 nM in patient-derived xenograft organoids (PDXOs)) via dual mechanisms: 1) cell cycle modulation, inducing G1 arrest through Cyclin D1 downregulation; and 2) intrinsic apoptosis induction, evidenced by caspase-3 cleavage and an elevated Bax/Bcl-2 ratio. ZJH-1 also showed potential to affect metastasis-related processes, as suggested by reduced activity of MMP-2/MMP-9 and reversed markers of epithelial-mesenchymal transition (EMT). Network pharmacology analysis predicted HSP90AA1 as a potential docking target of ZJH-1. Furthermore, protein expression analysis demonstrated that ZJH-1 upregulates disabled homolog 2 interacting protein (DAB2IP) and downregulates heat shock protein 90AA1 (HSP90AA1). In vivo, ZJH-1 (20 mg/kg, i.p.) significantly attenuated tumor growth in PC3 xenograft models (75 % volume reduction vs. controls) with no obvious weight loss or overt toxic side effects observed. These findings suggest that ZJH-1, a selective HDAC1 inhibitor, merits further investigation as a potential treatment for PCa.
    Keywords:  Antitumor; HDAC1 inhibitors; HSP90AA1; Histone deacetylases; Prostate cancer
    DOI:  https://doi.org/10.1016/j.cbi.2025.111777
  26. JNCI Cancer Spectr. 2025 Oct 14. pii: pkaf101. [Epub ahead of print]
    Exploring the feasibility of PP1-docking motif-mimetic cell-penetrating peptides for modulating prostate carcinogenesis.
    Renato M Rodrigues, Juliana Felgueiras, Sarah Jones, Vânia Camilo, Bárbara Matos, Carmen Jerónimo, John Howl, Margarida Fardilha.
       BACKGROUND: Once considered "undruggable," protein phosphatases are now recognised as potential therapeutic targets. The serine/threonine-protein phosphatase 1 (PP1) regulates key cellular processes and enhances androgen receptor (AR) activity in prostate cancer (PCa), even under castration-resistant conditions, suggesting a role in disease progression.
    METHODS: : LNCaP and PC3 cells were treated with peptides mimicking PP1 docking motifs in AR, alongside known bioportides (MSS1 and mitoparan). Cellular uptake was assessed by confocal microscopy and fluorescence assays. Viability was measured with PrestoBlue™, and AR/PSA expression was analysed by qRT-PCR and Western blot.
    RESULTS: Androgen Receptor sequence contains three PP1 docking motifs: KVFF (Binding Site 1 (BS1), HVVKW (BS2), and KPIYF (BS3). BS1 and BS2 peptides were modified for better solubility, while BS3 was combined with the Tat sequence to enhance cellular uptake. Fluorophore-conjugated peptides successfully entered cells, with AR-BS3 showing the highest internalisation in LNCaP cells (p = .0495). Treatment with the three different AR-BS peptides individually reduced cell viability in LNCaP and PC3 cells (p = .0352 and p = .0298, respectively). Combining AR-BS peptides significantly reduced cell viability, particularly with all three peptides together (LNCaP: 68%, p = .0369; PC3: 80%, p = .0369). No significant changes in AR or PSA expression were observed.
    CONCLUSION: Bioportides targeting PP1 docking motifs, especially when combined, decrease PCa cell viability, and additional PP1-interfering peptides such as MSS1 and mitoparan display potent cytotoxic effects. The absence of changes in AR/PSA expression highlights the need to further investigate their mechanisms of action.
    Keywords:  Androgen; Prostate Cancer; Protein Phosphatase 1; Receptors; bioportide; protein-protein interaction
    DOI:  https://doi.org/10.1093/jncics/pkaf101
  27. J Exp Clin Cancer Res. 2025 Oct 16. 44(1): 290
    Multi-layer stratified oncology platform utilizing transcriptomics, prostate cancer organoids, and modeling of drug response.
    Juening Kang, Panagiotis Chouvardas, Andrew Maalouf, Daniel Hanhart, Laura Fernández Cerro, Wanli Cheng, Eva Compérat, Katja Ovchinnikova, Rahel Etter, Michaela Medová, Ulrich Schneeberger, Beat Roth, George N Thalmann, Sofia Karkampouna, Marianna Kruithof-de Julio.
      The high intra-patient heterogeneity in multifocal primary prostate cancer (PCa) has curtailed the efficacy of current treatment options. By employing twin biopsies from multiple lesions with matched patient-derived organoids (PDO) models, the PCa molecular heterogeneity was investigated. We utilized genomics, transcriptomics and machine learning (ML) approaches to elucidate and predict the underlying mechanisms of pharmacological heterogeneity. Our data indicate a vulnerability of primary PCa organoids for small molecule inhibitors targeting receptor tyrosine kinases (MET, ALK, SRC). By exploring gene expression data from matched parental tissue in an unsupervised manner, we identified two distinct clusters of samples. Interestingly, the PDO drug responses were significantly different between the two clusters for 4/11 compounds tested. We developed a transcriptomics-based, cluster prediction model, which can accurately stratify samples into the two clusters. Notably, our prediction model is based on tissue profiles, therefore, it can be utilized to rapidly evaluate new cases and suggest promising drug candidates, even when PDO derivation is not feasible. Taken together, we propose a novel flexible stratified oncology approach that can swiftly and accurately highlight promising drug vulnerabilities of PCa patients.
    DOI:  https://doi.org/10.1186/s13046-025-03540-2
  28. Mol Cancer Res. 2025 Oct 13.
    Combined MYC Activation and PTEN Loss Drives Molecular Features of Aggressive Preinvasive Lesions in Mouse Prostate.
    Michael Rubenstein, Apurv Rege, Gretchen Hubbard, Danielle Cannady, Shreya Agarwal, Kevin Chen, Alex Estrada, Carolina Gomes Alexandre, Jessica Hicks, Tracy Jones, Qizhi Zheng, Srinivasan Yegnasubramanian, Charles J Bieberich, Angelo M De Marzo.
      Prostate cancer ranges from indolent to rapidly progressive. An elevated cell proliferation index portends poor outcomes, yet the molecular alterations essential for increased cell proliferation remain ill-defined. Gain of MYC combined with biallelic PTEN loss predicts prostate cancer mortality. Prior studies have shown that combined MYC overexpression and Pten loss, driven by the Hoxb13 locus, results in prostatic intraepithelial neoplastic (PIN) lesions that progress to metastatic disease (BMPC mice). Yet, single gene alterations in these mice result only in PIN. Herein, we performed transcriptomic profiling of PIN lesions from each of the 3 genotypes. While MYC alone resulted in increases in genes related to cell cycle regulation/cell division, combined MYC and Pten loss led to a further and more consistent increase, and a synergistic cell cycle progression. Increased ribosome biogenesis/translation are required for cell proliferation. While MYC alone increased 45S rRNA, and most components of the translation machinery, these were more strongly induced in BMPC mice. Surprisingly, Pten loss alone resulted in a downregulation of translation machinery genes, which could explain the absence of biallelic PTEN loss in human PIN and early carcinomas. Some MYC targets were increased only after Pten loss, indicating Pten loss increases MYC activity. Implications: These findings are that increased cell cycle and translational machinery gene induction may explain the synergy between MYC and PTEN loss for increasing prostate cancer cell proliferation and disease aggressiveness. Finally, these results provide further support for the therapeutic targeting of translation in prostate cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-1206
  29. Signal Transduct Target Ther. 2025 Oct 15. 10(1): 346
    In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance.
    Fei-Ya Yang, Ni-Yuan Zhang, Yang Yang, Dong Chen, Li-Yuan Wu, Wen-Kuan Wang, Hao-Xi Wang, Zhuan Wen, Ming-Ze Cai, Hao-Ze Li, Haojie Huang, Hong-Wei An, Hao Wang, Nian-Zeng Xing.
      Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s41392-025-02444-z
  30. Cancers (Basel). 2025 Oct 01. pii: 3208. [Epub ahead of print]17(19):
    Therapeutic Alliances for Optimizing the Management of Patients with Prostate Cancer: SOGUG Multidisciplinary Expert Panel Recommendations.
    Aránzazu González-Del-Alba, Claudio Martínez Ballesteros, José Ángel Arranz, Enrique Gallardo, Regina Gironés Sarrió, Fernando López Campos, Jesús Muñoz-Rodríguez, María José Méndez-Vidal, Alfonso Gómez de Iturriaga.
      A group of Spanish experts of different specialties participated in the ENFOCA2 project, promoted by the Spanish Oncology Genitourinary Group (SOGUG), which was designed to provide updated information on current and novel aspects contributing to the optimal care of prostate cancer (PCa) patients. In localized disease, it is important to implement strategic alliances with other institutions for improving adherence to active surveillance in low-risk groups and to explore genetic testing for a better indication of focal therapy. Local control of the disease should be maximized to prevent local failure and biochemical recurrence. In patients with locally advanced disease, with PSMA PET/CT-positive lesions in M0 staging on conventional imaging techniques, therapeutic decisions should be carefully evaluated due to insufficient evidence regarding the gold standard in this setting. In patients with metastatic castration-resistant PCa (mCRPC), assessment of BRCA somatic and germline mutations provides prognostic information and familial cancer risk and informs treatment decisions. Combinations of androgen receptor signaling inhibitor (ARSi) agents and poly-ADP ribose polymerase inhibitors (PARPi) are emerging alternatives for advanced PCa. The oldest segment of PCa patients (>70 years of age) may require geriatric assessment to evaluate physical and functional reserves, tailoring treatment to their individual characteristics and circumstances. The concept of a comprehensive multidisciplinary approach together with inter-center and/or inter-specialty therapeutic alliances should be implemented in the routine care of patients with PCa.
    Keywords:  biochemical recurrence; geriatric assessment; localized disease; locally advanced disease; metastatic disease; multidisciplinary team; prostate cancer; therapeutic alliances
    DOI:  https://doi.org/10.3390/cancers17193208
  31. Discov Oncol. 2025 Oct 15. 16(1): 1900
    The molecular aspects in prostatic cancer, unraveling the role of CDKs in prostate cancer progression.
    Zahra Farjami, Zahra Mohammadzadeh, Bita Saifi, Mahasti Tavakoli Nezhad, Mohammad Mehdi Akbarin.
       BACKGROUND: Prostate cancer (PCa) is one of the leading causes of morbidity and mortality in the world, it becomes imperative to investigate the molecular mechanisms underlying practical therapeutic approaches. Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression, and their dysregulation has been implicated in PCa.
    METHODS: This review synthesizes recent findings on CDK-mediated signaling pathways and their role in PCa progression. The overall goal of this review article is to elucidate the molecular mechanisms by which CDK molecules contribute to the development, progression, and metastasis of PCa.
    RESULTS: Elevated expression of CDK1, CDK3, CDK5, and CDK16 is associated with poorer outcomes, and specifically, high CDK3 expression correlates with shorter progression-free survival.
    CONCLUSIONS: Targeting CDKs, particularly CDK3 and CDK4/6, may represent a promising therapeutic strategy for PCa.
    Keywords:  CDK; Cell cycle inhibitors; Cyclins; Molecular pathogenesis; Prostate cancer
    DOI:  https://doi.org/10.1007/s12672-025-03605-w
  32. J Clin Invest. 2025 Oct 15. pii: e192883. [Epub ahead of print]135(20):
    RCC2 and CD24 cooperate to modulate prostate cancer progression through vimentin ubiquitination and β-catenin activation.
    Xuelian Cui, Yicun Wang, Chao Zhang, Zhichao Liu, Haiyan Yu, Lizhong Wang, Jiangbing Zhou, Runhua Liu.
      CD24 promotes prostate cancer progression and metastasis by disrupting the ARF-NPM interaction and impairing p53 signaling. However, the mechanisms underlying CD24-driven metastasis remain unclear. This study identifies a novel interaction between CD24 and Regulator of Chromosome Condensation 2 (RCC2), a protein involved in cell proliferation and migration. IHC analysis of prostate adenocarcinoma samples showed frequent coexpression of CD24 (49%) and RCC2 (82%) with a positive correlation between coexpression of CD24 (49%) and RCC2 (82%). Functional assays revealed complex roles: RCC2 KO suppressed proliferation but increased migration and invasion, while CD24 KO reduced both proliferation and migration. Dual KO of CD24 and RCC2 further inhibited proliferation but had varied effects on migration. In mouse xenografts, RCC2 KO increased lung metastasis without significantly affecting primary tumor growth, while CD24 KO reduced both tumor growth and metastasis. Mechanistically, RCC2 controls migration by promoting ubiquitination and degradation of vimentin, affecting cytoskeletal dynamics. In contrast, CD24 targets RCC2 for degradation, thereby regulating β-catenin signaling. Notably, RCC2 KO enhances β-catenin activity by suppressing inhibitors AXIN2 and APC, whereas CD24 KO inhibits this pathway. These findings reveal a regulatory loop where CD24 and RCC2 reciprocally control proliferation and metastasis, positioning the CD24-RCC2 axis as a promising therapeutic target in prostate cancer.
    Keywords:  Cell biology; Genetics; Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/JCI192883
  33. J Pharm Anal. 2025 Sep;15(9): 101232
    Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.
    Zhipeng Wang, Jie Wang, Dengxiong Li, Ruicheng Wu, Jianlin Huang, Luxia Ye, Zhouting Tuo, Qingxin Yu, Fanglin Shao, Dilinaer Wusiman, William C Cho, Siang Boon Koh, Wei Xiong, Dechao Feng.
      Prostate cancer is the most prevalent malignant tumor among men, ranking first in incidence and second in mortality globally. Novel hormone therapies (NHT) targeting the androgen receptor (AR) pathway have become the standard of care for metastatic prostate cancer. This review offers a comprehensive overview of NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, and rezvilutamide, which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life. Nevertheless, resistance to NHT remains a critical challenge. The mechanisms underlying resistance are complex, involving AR gene amplification, mutations, splice variants, increased intratumoral androgens, and AR-independent pathways such as the glucocorticoid receptor, neuroendocrine differentiation, DNA repair defects, autophagy, immune evasion, and activation of alternative signaling pathways. This review discusses these resistance mechanisms and examines strategies to counteract them, including sequential treatment with novel AR-targeted drugs, chemotherapy, poly ADP-ribose polymerase inhibitors, radionuclide therapy, bipolar androgen therapy, and approaches targeting specific resistance pathways. Future research should prioritize elucidating the molecular basis of NHT resistance, optimizing existing therapeutic strategies, and developing more effective combination regimens. Additionally, advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies. These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.
    Keywords:  Advanced prostate cancer; Androgen receptor; Drug resistance; Novel hormone therapies
    DOI:  https://doi.org/10.1016/j.jpha.2025.101232
  34. Cancer Causes Control. 2025 Oct 13.
    Differences in prostate cancer treatment receipt and timeliness of treatment between African American/Black and White Iowans.
    Gawain J Williams, Whitney E Zahnd.
       BACKGROUND: Non-Hispanic Black (NHB) men face higher prostate cancer (PCa) mortality rates compared to other racial/ethnic groups. Factors contributing to these disparities, particularly concerning healthcare system factors, remain uncertain. We investigate differences in treatment receipt and timeliness between NHB, non-Hispanic White (NHW) and Hispanic Iowans, examining variations across treatment facilities.
    METHODS: Demographic, tumor, treatment, and hospital characteristics of PCa patients 40-99 years were obtained from the Iowa Cancer Registry (2010-2020). We used logistic regression to estimate the odds of receiving definitive treatment, time to treatment, and the type of treatment received.
    RESULTS: Among 18,747 PCa patients, 18,197 (97.1%) were NHW, 550 (2.9%) NHB, and 155 Hispanic (0.83%). NHB men were younger. The odds of receiving definitive treatment among advanced stage patients were significantly lower for NHBs compared to NHWs (adjusted odds ratio-AOR- 0.39; 95% CI 0.26-0.59). More NHBs underwent PCa treatment at either NCI-designated or CoC-accredited facilities. NHBs receiving care at an NCI-designated center or at a non-accredited center were less likely to receive definitive treatment compared to NHWs. Furthermore, NHBs with advanced PCa had diminished odds of receiving definitive treatment regardless of the status of the treatment facility (NCI: AOR = 0.34; 95% CI 0.13 - 0.93; CoC only: AOR = 0.47; 95% CI 0.29 - 0.76; Neither: AOR 0.24; 95% CI 0.10-0.60).
    CONCLUSION: NHB men with an advanced staging had lower odds of receiving definitive treatment across treatment settings. Further research and intervention are needed to reduce these disparities and improve PCa outcomes.
    Keywords:  Cancer registry; Prostate cancer disparities; Racial disparities; Treatment disparities
    DOI:  https://doi.org/10.1007/s10552-025-02064-6
  35. Diagnostics (Basel). 2025 Oct 09. pii: 2546. [Epub ahead of print]15(19):
    Beyond Radiomics Alone: Enhancing Prostate Cancer Classification with ADC Ratio in a Multicenter Benchmarking Study.
    Dimitrios Samaras, Georgios Agrotis, Alexandros Vamvakas, Maria Vakalopoulou, Marianna Vlychou, Katerina Vassiou, Vasileios Tzortzis, Ioannis Tsougos.
      Background/Objectives: Radiomics enables extraction of quantitative imaging features to support non-invasive classification of prostate cancer (PCa). Accurate detection of clinically significant PCa (csPCa; Gleason score ≥ 3 + 4) is crucial for guiding treatment decisions. However, many studies explore limited feature selection, classifier, and harmonization combinations, and lack external validation. We aimed to systematically benchmark modeling pipelines and evaluate whether combining radiomics with the lesion-to-normal ADC ratio improves classification robustness and generalizability in multicenter datasets. Methods: Radiomic features were extracted from ADC maps using IBSI-compliant pipelines. Over 100 model configurations were tested, combining eight feature selection methods, fifteen classifiers, and two harmonization strategies across two scenarios: (1) repeated cross-validation on a multicenter dataset and (2) nested cross-validation with external testing on the PROSTATEx dataset. The ADC ratio was defined as the mean lesion ADC divided by contralateral normal tissue ADC, by placing two identical ROIs in each side, enabling patient-specific normalization. Results: In Scenario 1, the best model combined radiomics, ADC ratio, LASSO, and Naïve Bayes (AUC-PR = 0.844 ± 0.040). In Scenario 2, the top-performing configuration used Recursive Feature Elimination (RFE) and Boosted GLM (a generalized linear model trained with boosting), generalizing well to the external set (AUC-PR = 0.722; F1 = 0.741). ComBat harmonization improved calibration but not external discrimination. Frequently selected features were texture-based (GLCM, GLSZM) from wavelet- and LoG-filtered ADC maps. Conclusions: Integrating radiomics with the ADC ratio improves csPCa classification and enhances generalizability, supporting its potential role as a robust, clinically interpretable imaging biomarker in multicenter MRI studies.
    Keywords:  ADC ratio; ComBat harmonization; MRI; classification; feature selection; machine learning; multicenter study; prostate cancer; radiomics
    DOI:  https://doi.org/10.3390/diagnostics15192546
  36. Quant Imaging Med Surg. 2025 Oct 01. 15(10): 9071-9084
    Biparametric magnetic resonance imaging-based radiomics model can improve the detection of dense and sparse prostate cancers.
    Bingni Zhou, Ting Wang, Zhangzhe Chen, Hong Lv, Hualei Gan, Rong Li, Liangping Zhou, Xiaohang Liu, Yajia Gu.
       Background: Prostate cancer (PCa) tissues are heterogeneous. The tumor lesion could be either the dense focus consisting of high proportion of malignant glands or the sparse focus consisting of a mixture of scattered tumor glands and normal tissue. The different growth patterns will affect the detection of PCa. The detection rate of the sparse PCa is far lower than that of the dense PCa. This study aimed to explore the value of radiomics based on biparametric magnetic resonance imaging (bpMRI) in the detection of dense and sparse PCa lesions.
    Methods: A total of 372 PCa lesions of 156 patients from two centers were defined as "sparse" or "dense" according to whole-mount sections and then delineated on bpMR images. For each lesion, 2,553 radiomics features were extracted from images. The optimal radiomics features were selected by one-way analysis of variance (ANOVA) and least absolute shrinkage and selection operator (LASSO) regression. The radiomics models constructed by the random forest classifier and the average apparent diffusion coefficient (ADC) value model were established for the peripheral zone (PZ) and the transitional zone (TZ) to detect dense lesions, sparse lesions, and noncancerous tissues. The areas under the curve (AUCs) and DeLong tests were used to analyze the performance of the models.
    Results: In the PZ, the AUCs of the radiomics model (external validation set) for noncancerous tissue, dense lesion, and sparse lesion detection were 0.91, 0.98, and 0.88, respectively, and those of the average ADC value model were 0.85, 0.73, and 0.62, respectively. In the TZ, those of the radiomics model were 0.92, 0.93, and 0.88, respectively, and those of the average ADC value model were 0.81, 0.83, and 0.52, respectively. Compared with that of the average ADC value model, the AUC of the radiomics model in the diagnosis of sparse lesions significantly differed (P<0.05). In the detection of dense lesions, there were significant differences in the training set (P<0.05).
    Conclusions: The radiomics model based on bpMRI can effectively improve the detection of PCa lesions, especially sparse lesions, and significantly reduce missed diagnoses.
    Keywords:  Prostate cancer (PCa); biparametric magnetic resonance imaging (bpMRI); radiomics
    DOI:  https://doi.org/10.21037/qims-2024-2912
  37. Molecules. 2025 Oct 02. pii: 3957. [Epub ahead of print]30(19):
    Preclinical Theranostic Profiling of [64Cu]Cu-Acetate in Prostate Cancer.
    Sadaf Ghanaatgar Kasbi, Martin Savard, Céléna Dubuc, Yves Dory, Brigitte Guérin, Fernand Gobeil.
      Copper plays a critical role in cancer biology, with tumor cells exhibiting abnormal copper metabolism that drives proliferation and tumor growth. A limited number of preclinical and clinical studies have reported promising theranostic potential of copper-based radionuclides, such as 64Cu, for both diagnostic imaging and targeted radiotherapy in diverse cancers, including prostate cancer (PCa). In this work, we evaluated the cellular uptake and antitumor efficacy of [64Cu]Cu-acetate using both cellular and animal models of PCa. Uptake assays revealed that ~70% of the administered dose (10 kBq) was internalized by PC-3 cells within 24 h, predominantly localizing to the cytoplasm, with around 9% detected in the nucleus. These results were corroborated by comparable natural Cu-acetate uptake levels (at equimolar dose) in PC-3 cells, as quantified by ICP-MS. Clonogenic assays revealed a dose-dependent reduction in survival following treatment with [64Cu]Cu-acetate (3 and 6 MBq), whereas its non-radioactive counterpart [NatCu]Cu-acetate, even at excess concentrations (10 µM), had no significant effect. Ex vivo biodistribution studies showed selective tumor accumulation/retention alongside expected hepatic uptake. Clear tumor visualization was achieved using μPET imaging with [64Cu]Cu-acetate (10 MBq iv). A single higher dose (65 MBq iv) effectively reduced tumor growth in a subcutaneous PC-3 xenograft mouse model, without systemic toxicity, as evidenced by stable body weight. Together, these results further support the theranostic potential of [64Cu]Cu in PCa.
    Keywords:  copper-64; mice; prostate cancer; radiopharmaceuticals; theranostics
    DOI:  https://doi.org/10.3390/molecules30193957
  38. Front Oncol. 2025 ;15 1650378
    Time and cost burden associated with docetaxel in patients with metastatic castration-sensitive prostate cancer initiating an androgen receptor pathway inhibitor-based regimen.
    Daniel Sentana-Lledo, Arjun Gupta, Carmine Rossi, Sabree Burbage, Jill Korsiak, Lilian Diaz, Gordon Wong, Dominic Pilon, Ibrahim Khilfeh, Alicia K Morgans.
       Background: The triplet combination of chemotherapy (docetaxel), androgen receptor pathway inhibitors (ARPI), and androgen deprivation therapy has recently become a recommended approach to treat metastatic castration-sensitive prostate cancer (mCSPC). This study aimed to compare the incremental time and cost burden of adding docetaxel to ARPI-based treatment among patients with mCSPC receiving chemotherapy-containing regimens (CCR) and non-chemotherapy-containing regimens (NCR) in the United States.
    Methods: Clinical data from community urology practices linked with claims data (1/1/2016-12/31/2023) were used to select patients initiating a CCR or NCR. Outcomes, including time spent managing mCSPC (days with prostate cancer-related resource utilization or management care) and healthcare costs, were compared between balanced cohorts using weighted multivariable Poisson and linear regressions.
    Results: 126 CCR and 837 NCR patients (mean age 64.7 years, 52.6% White, 14.4% Black) were followed for a mean of 6.3 (CCR) and 6.8 (NCR) months. The CCR cohort spent on average 4.1 days per-patient-per-month (PPPM) managing mCSPC vs 3.3 days PPPM in the NCR cohort (rate ratio: 1.18; 95% confidence interval [CI]; 1.03, 1.34). Mean all-cause total healthcare costs were $17,833 PPPM in the CCR cohort and $11,527 PPPM in the NCR cohort (weighted adjusted cost difference: $6,184; 95% CI: 3,515, 8,517).
    Conclusions: Patients initiating a CCR experienced greater time burden managing mCSPC and higher healthcare costs than those initiating an NCR. These findings support counseling expressing these differences in burden in mCSPC treatment decision-making conversations.
    Keywords:  androgen receptor antagonists; chemotherapy; hormone receptor agonists; mCSPC; prostate neoplasms; time burden; triplet therapy
    DOI:  https://doi.org/10.3389/fonc.2025.1650378
  39. Front Genet. 2025 ;16 1604113
    Developing prognostic models for cholesterol-related genes linked with immune infiltration in prostate cancer.
    Jie Wu.
       Background: Prostate cancer has a high incidence and a low 5-year survival rate. We aimed to combine cholesterol- and immune-related genes to screen prostate cancer prognosis-related genes and construct a prognostic risk model.
    Methods: We obtained publicly released clinical data of prostate cancer through The Cancer Genome Atlas. Cholesterol- and immune-related genes were separately collected from the mSigDB and ImmPort databases. The prognostic model based on the immune-cholesterol-related differentially expressed mRNAs (DEmRNAs) network was constructed by univariate and multivariate Cox regression methods. Gene set enrichment analysis (GSEA), mutation landscape analysis, and immune infiltration analysis were carried out to investigate the role of immune-cholesterol-related DEmRNAs in prostate cancer.
    Results: We identified 11 immune-cholesterogenic-related DEmRNAs (C2orf88, TRPM4, SAPCD2, RHPN1, RAC3, APOF, PTGS2, TSPAN1, KLK4, ENTPD5, and C1orf64) as risk factors that were related to the occurrence and development of prostate cancer by bioinformatics analysis. Immune infiltration analysis suggested immune-cholesterol-related DEmRNAs may act in an immunomodulatory role for treatment decisions. The proportion of plasma cells, memory resting CD4 T cells, and neutrophils in the low-risk group was significantly higher than that in the high-risk group (p < 0.05). The GSEA revealed DEmRNAs were enriched in 58 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, consisting of hematopoietic cell lineage, hypertrophic cardiomyopathy, and the JAK-STAT signaling pathway. The Gleason score of the high-risk group showed a significant difference from that of the low-risk group after clinical data analysis (P < 0.05).
    Conclusion: The prognostic risk model and nomogram constructed based on the immune-cholesterol-related genes had a great prognostic performance for prostate cancer.
    Keywords:  cholesterol; immune-related genes; immunity; prognosis; prostate cancer
    DOI:  https://doi.org/10.3389/fgene.2025.1604113
  40. Biomater Adv. 2025 Oct 07. pii: S2772-9508(25)00369-3. [Epub ahead of print]180 214542
    PEGylated liposomes co-encapsulating darolutamide and hesperetin for enhanced prostate cancer therapy: 2D, 3D PC3 models and in-vivo evaluation.
    Ruchita Patil, Ekta Pardhi, Rahul Khemchandani, Avinash Pawar, Gananadhamu Smanthula, Neelesh Kumar Mehra.
      In this study, a darolutamide and hesperetin co-loaded PEGylated liposomal formulation (DHLP) was developed for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). The formulation was prepared using the ethanol injection method, followed by membrane extrusion through a 100 nm polycarbonate filter to ensure size uniformity. The optimized DHLP liposomal formulation exhibited a clear bluish appearance, with a mean particle size of 106.5 ± 3.2 nm, a polydispersity index of 0.128 ± 0.023, and a zeta potential of -14.10 ± 0.25 mV, indicating colloidal stability and uniformity. Spherical morphology was confirmed through microscopic analysis. High encapsulation efficiencies were achieved for both DA (90.1 ± 3.3 %) and HE (91.3 ± 2.7 %). For both medication, in vitro drug release experiments showed a sustained release profile from the DHLP. Cytotoxicity assessment in PC3 prostate cancer cells revealed a 2.83-fold increase in cytotoxicity compared to free DA solution, a 3.89-fold increase compared to free HE solution, and a 1.47-fold improvement over the combined DA-HE solution. The combination index value of 0.89 confirmed synergistic anticancer activity. DHLPs inhibited cell migration, increased ROS generation, and reduced 3D spheroid size, with enhanced cellular uptake contributing to improved therapeutic efficacy. In-vivo pharmacokinetic studies in BALB/c mice demonstrated a 1.7- and 3.4-fold increase in the plasma half-life of DA and HE, respectively, compared to their free drug solutions. Biodistribution studies revealed reduced accumulation of DHLP in vital organs compared to the free drug solution. Acute toxicity assessment at three dose levels showed no histopathological alterations, indicating a favorable safety profile. These results imply that DHLP is a potential nanocarrier system for the effective management of prostate cancer.
    Keywords:  Darolutamide; Hesperetin; Liposome; PEGylation; Pharmacokinetic
    DOI:  https://doi.org/10.1016/j.bioadv.2025.214542
  41. Chin Med J (Engl). 2025 Oct 16.
    Androgen receptors protect against thoracic aortic dissection via inhibiting ferroptosis of vascular smooth muscle cells in male patients.
    Qihong Ni, Yuli Wang, Haozhe Qi, Yongjie Yao, Zhexin Lu, Weilun Wang, Shuofei Yang, Jiaquan Chen, Yinan Li, Lei Lyv, Yiping Zhao, Meng Ye, Guanhua Xue, Wai Ho Tang, Yizhou Ye, Xiangjiang Guo, Lan Zhang.
       BACKGROUND: The development of thoracic aortic dissection (TAD) is closely associated with the loss of vascular smooth muscle cells (VSMCs). Androgen receptor (AR) signaling has increasingly been recognized as an important regulator of cell death in prostate cancer. However, the role of AR signaling in the development of TAD in men remains unknown.
    METHODS: The expression of AR was analyzed in clinical specimens obtained from TAD patients undergoing surgical aortic replacement and control subjects receiving heart transplantation. Using β-aminopropionitrile (BAPN)-induced aortic dissection mouse models, we systematically investigated the protective role of AR through multiple approaches. Histopathological evaluation was performed using immunohistochemistry and immunofluorescence. Primary vascular smooth muscle cells were isolated for functional studies including AR knockdown, ferroptosis assessment, and metabolic profiling. Mechanistic insights were gained through chromatin immunoprecipitation, luciferase reporter assays, and RNA stability tests. Seahorse extracellular flux analysis and targeted metabolomics were employed to characterize metabolic alterations.
    RESULTS: The expression of AR in VSMCs was downregulated in both clinical samples and animal models of TAD. Using in vitro and in vivo models, we demonstrate a novel function of AR that inhibits ferroptosis in VSMC by promoting excessive lipid peroxidation. Mechanistically, we show that AR counter-regulates the expression levels of acyl-CoA synthetases ACSL3 and ACSL4 in VSMCs. AR acts as a transcriptional regulator to promote the transcription of ACSL3 gene while inhibiting the transcription of the ACSL4 gene, both of which inhibit lipid peroxidation and ferroptosis. Importantly, activating AR signaling is beneficial in preventing TAD from developing and progressing in the animal model.
    CONCLUSIONS: Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.
    Keywords:  Androgen receptor; Ferroptosis; Lipid peroxidation; Thoracic aortic dissection; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1097/CM9.0000000000003749
  42. J Dent Res. 2025 Oct 18. 220345251370240
    Periodontitis Promotes OSCC and Prostate Cancer Progression and Immunosuppression by Skewing Myeloid Differentiation of HSPCs.
    F Nie, S Wang, H Tian, J Zhang, Q Yin, J Ju, P Gong, J Liu, P Yang, C Yang.
      Inflammation is an enabling characteristic that contributes to the acquisition of hallmarks of cancer. Epidemiological studies have suggested a potential connection between periodontitis and increased risk of cancer. However, the underlying mechanisms of this connection remain insufficiently studied. Here, we found that periodontitis promoted the progression of oral squamous cell carcinoma and prostate cancer and fostered an immunosuppressive tumor microenvironment (iTME) characterized by expanded myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and regulatory T cells in mouse models. Periodontitis also enhanced the immunosuppressive function of MDSCs and decreased the infiltration of CD8+ T cells. Moreover, periodontitis-induced systemic inflammation remodeled the bone marrow (BM) ecosystem, resulting in myeloid-biased hematopoiesis, which was accompanied by expansion of hematopoietic progenitors (LSK), multipotent progenitor 3 (MPP3), and granulocyte-monocyte precursors, followed by the subsequent augmentation of myeloid cell production. Mechanistically, interleukin (IL)-1 signaling, triggered by periodontitis, induced alterations in the myelopoiesis program. The conditional inhibition of IL-1R1 in the BM attenuated the tumor-promoting effect of periodontitis, diminished abnormal myeloid overproduction, and improved the TME. Thus, these findings reveal that periodontitis remotely induces a myeloid bias in hematopoietic stem and progenitor cells, and that the IL-1-mediated periodontitis-BM axis serves as a critical mechanism for periodontitis-facilitated tumor development and iTME establishment.
    Keywords:  Periodontal diseases; hematopoietic stem cells; mouth neoplasms; myeloid cells; prostatic neoplasms; tumor microenvironment
    DOI:  https://doi.org/10.1177/00220345251370240
  43. Ann Surg Oncol. 2025 Oct 15.
    Evaluating the Clinical Competence of Large Language Models in Prostate Cancer Management: A Comparative Study of DeepSeek-R1 and ChatGPT.
    Rongkang Li, Anguo Zhao, Lei Peng, Hongjin Shi, Jiadong Zhao, Zhilin Li, Rui Liang, Haifeng Wang.
       BACKGROUND: Large language models (LLMs) have gained prominence in medical applications, yet their performance in specialized clinical tasks remains underexplored. Prostate cancer, a complex malignancy requiring guideline-based management, presents a rigorous testbed for evaluating artificial intelligence (AI)-assisted decision-making. This study compared the clinical accuracy, reasoning ability, and language quality of DeepSeek-R1 and ChatGPT variants in addressing prostate cancer diagnosis and treatment.
    METHODS: A dataset of 98 prostate cancer multiple-choice questions from MedQA, MedMCQA, and China's National Medical Licensing Examination was constructed, alongside three real-world clinical cases. Responses were generated by five LLMs (DeepSeek-V3, DeepSeek-R1, ChatGPT-4o, -o3, -o4-mini) and evaluated for accuracy across three repeated runs. For case-based simulations, only R1 and o3 were compared with practicing urologists. A Clinical Decision Quality Assessment Scale (CDQAS) assessed outputs across four domains: readability, medical knowledge accuracy, diagnostic test appropriateness, and logical coherence. Blinded scoring was performed by senior urologic oncologists. Statistical analyses used one-way ANOVA with GraphPad Prism v10.1.2, Boston, Massachusetts, USA.
    RESULTS: DeepSeek-R1 achieved the highest accuracy (96.60 %) on multiple-choice tasks, significantly outperforming the other models (p < 0.05 to <0.0001). In simulated case evaluations, both R1 and o3 performed comparably with physicians in overall readability and diagnostic appropriateness. Whereas R1 demonstrated superior guideline compliance and evidence-based reasoning, o3 showed advantages in workflow clarity, sequencing, and response fluency. However, o3 generated fewer explicit errors than R1. Human clinicians maintained strengths in terminology precision and logical reasoning.
    CONCLUSION: DeepSeek-R1 and ChatGPT-o3 exhibit complementary strengths in prostate cancer clinical decision-making, with R1 favoring factual accuracy and o3 excelling in expressive clarity. Although both models approach human-level performance in structured evaluations, human oversight and continued domain-specific optimization remain essential for their safe and effective integration into clinical workflows.
    Keywords:  ChatGPT; Clinical decision-making; DeepSeek-R1; Large language models (LLMs); Prostate cancer
    DOI:  https://doi.org/10.1245/s10434-025-18492-2
  44. Diagnostics (Basel). 2025 Sep 24. pii: 2434. [Epub ahead of print]15(19):
    Prognostic Potential of Cancer-Associated Fibroblast Surface Markers and Their Specific DNA Methylation in Prostate Cancer.
    Mark Jain, Olga Nesterova, Mikhail Varentsov, Nina Oleynikova, Aleksandra Vasiukova, Sofia Navruzova, German Golubin, Larisa Samokhodskaya, Pavel Malkov, Armais Kamalov.
      Background: Cancer-associated fibroblasts (CAFs) are a key component of the prostate cancer (PCa) microenvironment, the abundance of which is often linked to poor prognosis. The surface markers for CAFs are mostly established, yet our current knowledge of epigenetic alterations in them remains limited. The aim of this study was to evaluate the relationship between CAF-specific DNA methylation, their abundance and the PCa prognosis. Methods: The study included 88 PCa patients with known presence or absence of a biochemical recurrence within a 6-year period. Resected PCa tissue was assessed for the surface expression of FAP, PDGFRb, CD90, and POST, and for the methylation of EDARADD, GATA6, and PITX2 genes using qPCR and ddPCR. Results: The surface expression of FAP, PDGFRb and CD90 was associated with a higher Gleason score (p < 0.05). The analytical sensitivity of ddPCR was superior to qPCR; results obtained using ddPCR demonstrated a more significant association with clinical features of PCa. EDARADD methylation and PDGFRb expression were associated with a risk of biochemical recurrence (HR-0.961 [95% CI: 0.931-0.991] and HR-2.313 [95% CI: 1.054-5.088]; p < 0.05, respectively). Conclusions: Upon further validation, the abundance of CAFs and their specific methylation might become a promising tool for the assessment of prognosis in PCa after radical treatment.
    Keywords:  DNA methylation; biochemical recurrence; cancer-associated fibroblasts; prognosis; prognostic biomarker; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/diagnostics15192434
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