bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–11–02
forty-two papers selected by
Grigor Varuzhanyan, UCLA
  1. Low-dose polystyrene microplastics exposure promotes human prostate cancer cell proliferation via GPX4‑mediated ferroptosis.
  2. Rutin Suppresses EMT and Induces Mitochondrial Biogenesis via ER Stress-linked AMPK/SIRT1 Signaling in Prostate Cancer Cells.
  3. ERRγ impedes neuroendocrine prostate cancer development.
  4. Proline Intake Dampens Radiosensitivity in Prostate Cancer Cells by Targeting PRODH/MAPK Pathway.
  5. ‌Liquid-Liquid Phase Separation of AR Orchestrated by Melatonin Sensitizes Prostate Cancer to Ferroptosis Via MCM5/NRF2 Axis Collapse.
  6. The Antiproliferative Activity of Tatridin A Against Prostate Cancer Cells Is Lost in Acid Medium by Transformation to Desacetyl-β-Cyclopyrethrosin.
  7. HOXB13 interactome in prostate cancer cells: biochemical and functional interactions between the transcription factors HOXB13 and TBX3.
  8. Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.
  9. Research Advances in Cancer-Associated Fibroblasts in Prostate Cancer Progression.
  10. Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer.
  11. Transcription Factor Dynamics in Neuroendocrine Prostate Cancer Development.
  12. Targeting CXCR2 in prostate cancer cells can block CD47-SIRPα interaction and reverse M2 macrophage polarization in the TME.
  13. Anti-neoplastic effects of the antipsychotic drug penfluridol in preclinical prostate cancer models.
  14. Global Profiling of Lysine Lactylation in Prostate Cancer Cells.
  15. HER2 as a molecular trojan horse in prostate cancer: mechanistic insights and therapeutic unlocks.
  16. Lipid Metabolic Reprogramming During Progression to Castration-resistant Prostate Cancer Identified by Quantitative Proteomics.
  17. Mechanistic insights into SLAMF8-mediated prostate cancer metastasis via the TLR4-NF-κB pathway.
  18. Prostate cancer drug: NICE approves better tolerated combination for advanced cases.
  19. Computational discovery of resiniferatoxin and euphol as potential androgen receptor inhibitors for prostate cancer therapy.
  20. Antitumor, biological and nonlinear optical activities of novel thiazolidines.
  21. 3-acetyl-11-keto-β-boswellic acid and chitosan-Ag nanoparticles for synergistic tumor-resident bacteria mediated prostate cancer therapy.
  22. SCAMP3 and EPS8 Cooperatively Regulate EGFR Signaling to Promote Enzalutamide Resistance and Metastatic Potential in Prostate Cancer.
  23. Cytotoxicity of Mimusops caffra-Based Ursolic Acid, Oleanolic Acid and Derivatives Against Human Cancerous and Non-Cancerous Cell Lines.
  24. Treatment-Response Prediction for Metastatic Castrate-Resistant Prostate Cancer Using PSMA PET.
  25. PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy.
  26. Circular RNA circSLC39A10 promotes prostate cancer progression by activating Wnt signaling via the miR-936/PROX1/β-catenin axis.
  27. Biomimetic bone niche reconstructs proliferation-inhibited and therapy-resistant bone-metastatic prostate cancer.
  28. The Association Between Selenium Levels and Risk of Prostate Cancer: A Systematic Review and Meta-analysis of 16,964 Participants (1980-2024).
  29. Investigation of importance Raman shifts in liquid biopsy diagnostics of prostate cancer.
  30. Cyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells.
  31. The nervous system in prostate cancer: A basic science and clinical perspective.
  32. Identifying the optimal time point for adaptive re-planning in prostate cancer radiotherapy to minimise rectal toxicity using normal tissue imaging biomarkers.
  33. Multidisciplinary therapy targeting histological heterogeneity in prostate cancer with bone marrow carcinomatosis: A case report.
  34. TMPRSS2 Expression in Lung Tissue of Prostatic Adenocarcinoma Patients: Androgen Deprivation Therapy and Relevance to SARS-CoV-2 Infection.
  35. Association Between Obstructive Sleep Apnea and Prostate Cancer: NHANES and the Mendelian Randomization Study.
  36. Verbascoside Suppresses Epithelial-Mesenchymal Transition and Mitochondrial Biogenesis by Targeting Anti-senescence Signaling in Castration-resistant Prostate Cancer.
  37. Assessing the relationship between cardiometabolic diseases and the risk of developing aggressive prostate cancer: a systematic review and meta-analysis.
  38. Profiling Inhibitor Scaffolds for the Cancer Target Jumonji-C Domain-Containing Protein 6.
  39. Are pNF-H, IL-6, BDNF, and NSP Reliable Biomarkers of Cognitive Function in Prostate Cancer Patients?
  40. Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.
  41. Efficacy and safety of apalutamide, abiraterone acetate, and bicalutamide in the treatment of metastatic hormone-sensitive prostate cancer.
  42. Multimodal integration of [18F]PSMA-1007 PET/CT semiquantitative parameters and clinicopathological data for predicting prostate cancer metastasis.
  1. Ecotoxicol Environ Saf. 2025 Oct 27. pii: S0147-6513(25)01630-6. [Epub ahead of print]306 119285
    Low-dose polystyrene microplastics exposure promotes human prostate cancer cell proliferation via GPX4‑mediated ferroptosis.
    Jingmo Li, Chenyao Deng, Wenyu Zou, Xindi Jiang, Yinuo Dong, Zidi Yan, Hui Jiang, Jia Zheng, Zirun Jin.
      Microplastics are increasingly recognized as potential threats to human health. In our previous study, polystyrene microplastics (PS-MPs) were detected in both para-tumor and tumor tissues of human prostate samples, with significantly higher abundance observed in tumor tissues compared to their paired para-tumor counterparts. However, whether and how PS-MPs contribute to the progression of prostate cancer remains poorly understood. This study aims to investigate the effects and underlying mechanisms of PS-MPs exposure on the proliferation of human prostate cancer cells. To this end, we exposed both the human prostate cancer cell line LNCaP and primary cultured human prostate cancer cells to varying doses of 1-μm-diameter PS-MPs. Our results showed that low-dose (0.1 μg/mL) PS-MPs exposure for 48 significantly promoted the proliferation of LNCaP cells. Additionally, PS-MPs exposure altered the expression of certain inflammatory factors and induced oxidative stress in LNCaP cells. We also observed upregulation of GPX4 and ACSL4 in LNCaP cells and primary prostate cancer cells following PS-MPs exposure. Notably, GPX4 knockdown reversed the effects of PS-MPs on reactive oxygen species (ROS) levels, lipid peroxidation, and glutathione content, likely by promoting ferroptosis. Taken together, our findings highlight a critical role for ferroptosis in PS-MPs-induced proliferation of human prostate cancer cells under low-dose exposure.
    Keywords:  Ferroptosis; GPX4; Polystyrene microplastic; Proliferation; Prostate cancer
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119285
  2. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 971-990
    Rutin Suppresses EMT and Induces Mitochondrial Biogenesis via ER Stress-linked AMPK/SIRT1 Signaling in Prostate Cancer Cells.
    Sih-Han Chen, Richard C Wu, Wei-Lun Huang, Chun-Hsien Wu, Hsing-Chia Mai, Yu-Lin Yang, Pei-Fang Hsieh, Victor C Lin, Chien-Hui Ou.
       BACKGROUND/AIM: Prostate cancer is the second most commonly diagnosed malignancy and a leading cause of cancer-related mortality among men worldwide. While early-stage disease can often be managed effectively, advanced and treatment-resistant forms such as castration-resistant prostate cancer (CRPC) remain a major therapeutic challenge. Novel therapeutic strategies targeting alternative pathways are therefore urgently needed. Rutin, a natural flavonoid abundant in fruits and vegetables, has demonstrated antioxidant and anticancer properties. This study aimed to investigate the anticancer effects of Rutin in prostate cancer cells, focusing on epithelial-mesenchymal transition (EMT), mitochondrial biogenesis, and endoplasmic reticulum (ER) stress-linked signaling.
    MATERIALS AND METHODS: Four prostate cancer cell lines (PC-3, DU-145, LNCaP, and LNCaP-Enz) were treated with rutin. Cell proliferation was assessed, and EMT markers [E-cadherin, α-smooth muscle actin (α-SMA), Snail, Slug], mitochondrial biogenesis-related proteins (AMPK, SIRT1, PGC-1α, NRF1, TFAM), and ER stress markers (BiP, IRE1, PERK, ATF6) were analyzed by standard molecular and cellular assays. Co-treatment with the ER stress inhibitor TUDCA and the eIF2α phosphorylation modulator Salubrinal was performed to determine pathway involvement.
    RESULTS: Rutin significantly suppressed cell proliferation and EMT in all tested prostate cancer cell lines, as indicated by increased E-cadherin expression and decreased α-SMA, Snail, and Slug. It also promoted mitochondrial biogenesis through the up-regulation of AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In parallel, rutin reduced ER stress marker expression, and these effects were reversed by co-treatment with TUDCA or Salubrinal.
    CONCLUSION: Rutin inhibits prostate cancer progression by suppressing EMT, inducing mitochondrial biogenesis, and acting via ER stress-linked AMPK/SIRT1 signaling. These findings suggest that Rutin may serve as a potential therapeutic candidate for advanced prostate cancer.
    Keywords:  AMPK; EMT; ER stress; Rutin; mitochondrial biogenesis; prostate cancer
    DOI:  https://doi.org/10.21873/cgp.20550
  3. Genes Dev. 2025 Oct 29.
    ERRγ impedes neuroendocrine prostate cancer development.
    Ting Li, Catherine R Dufour, Lingwei Han, Anthony Alfonso, Mirna Farhat, Annabelle Beaumier, Qian Chen, Jin-Jian Lu, Vincent Giguère.
      Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood, and effective treatments remain to be discovered. Here, we report that loss of the nuclear receptor ERRγ promotes neuroendocrine differentiation in a Pten-deficient mouse model of prostate adenocarcinoma. These findings were recapitulated in advanced cellular and xenograft models of human prostate cancer. Critically, we show that ERRγ gain of function can reverse instilled NEPC features accompanied by suppression of growth and oncogenic metabolic reprogramming. Activation of a neuroendocrine transcriptional program enabled by ERRγ deficiency unveiled a targetable vulnerability exploited by the combined pharmacological inhibition of EZH2 and RET kinase that effectively inhibited the growth of ERRγ-deficient tumor organoids and cells. Collectively, our findings demonstrate that ERRγ downregulation facilitates prostate cancer adeno-to-neuroendocrine transformation and offer potential therapeutic strategies to prevent/treat the development of poor outcome NEPC.
    Keywords:  ChIP-seq; EZH2; NEPC; PROX1; RET; RNA-seq; adenocarcinoma; lineage plasticity; metabolism; nuclear receptor; transcription
    DOI:  https://doi.org/10.1101/gad.353024.125
  4. Radiat Res. 2025 Oct 31.
    Proline Intake Dampens Radiosensitivity in Prostate Cancer Cells by Targeting PRODH/MAPK Pathway.
    Lei Chang, Xinzhou Deng, Shan Jiang, Cangyu Wang, Jingjing Chai, Le Zhou, Chao Tian, Yuanhui Tang, Zhiguo Luo, Lihua Duan, Yutao Yan.
      Radiotherapy remains a standard treatment for prostate cancer (PCa), inducing tumor cell death and apoptosis. However, its efficacy depends on various factors, including tumor cell metabolism. In this study, we investigated whether alterations in proline metabolism influence the response of prostate cancer cells to radiation. The radiosensitivity of LNCaP and C4-2 cells after X-ray irradiation was assessed using colony formation and tumor-sphere assays, while Matrigel invasion assays evaluated in vitro cell invasion. We then examined the effect of radiation on proline dehydrogenase (PRODH) expression and MAPK/p-MAPK signaling via Western blotting. To further explore the role of proline metabolism in radiation response, we tested the impact of exogenous proline supplementation and PRODH knockdown on radiation efficacy in LNCaP and C4-2 cells using the same assays. Finally, in vivo validation was performed using xenograft tumor models in nude mice to determine how proline and PRODH modulation influences radiation outcomes. Our results demonstrated that X-ray irradiation significantly inhibited prostate cancer cell growth and invasion. However, this effect was attenuated by exogenous proline supplementation. Following irradiation, proline dehydrogenase (PRODH) expression was upregulated, while phosphorylated MAPK (p-MAPK) levels were downregulated. Notably, the suppressive effect of proline on radiation efficacy was abolished upon PRODH knockdown, suggesting a key role for proline metabolism in radiation response. In vivo studies further supported these findings: X-ray irradiation effectively suppressed tumor growth in xenograft mouse models, but this therapeutic effect was diminished when mice were treated with proline solution. These observations align with our in vitro data, reinforcing the modulatory role of proline metabolism in radiosensitivity. While radiotherapy demonstrates robust antitumor effects in prostate cancer, our findings reveal that proline metabolism significantly impairs radiation efficacy in both cellular and animal models.
    DOI:  https://doi.org/10.1667/RADE-25-00171.1
  5. J Pineal Res. 2025 Nov;77(6): e70094
    ‌Liquid-Liquid Phase Separation of AR Orchestrated by Melatonin Sensitizes Prostate Cancer to Ferroptosis Via MCM5/NRF2 Axis Collapse.
    Xianyanling Yi, Zeyu Han, Yaxiong Tang, Jin Li, Xuanji Li, Hang Xu, Xiaonan Zheng, Dazhou Liao, Hong Li, Qiang Wei, Lu Yang, Jianzhong Ai.
      The treatment of prostate cancer (PCa) remains challenging, and while melatonin (MEL) has demonstrated therapeutic potential, its precise mechanisms require further elucidation. Through integrated in vitro, in vivo, and bioinformatics analyses, this study demonstrated that MEL functioned as a novel ferroptosis inducer in PCa by disrupting androgen receptor (AR) liquid-liquid phase separation (LLPS). We found that MEL effectively inhibited PCa proliferation, migration, and invasion in vitro while suppressing tumor growth safely in mice models. Mechanistically, MEL impaired AR LLPS dynamics, reducing AR-driven transcription of minichromosome maintenance protein 5 (MCM5). MCM5 was a clinically relevant biomarker associated with aggressive PCa and poor survival. Crucially, downregulated MCM5 attenuated its physical interaction with NRF2, leading to uncontrolled activation of the NRF2/HMOX1 pathway, GPX4 suppression, and accumulation of ferroptosis hallmarks. These findings defined an AR/MCM5/NRF2 axis regulating ferroptosis susceptibility, establishing MEL as the first-reported ferroptosis inducer that expands the mechanistic foundation and therapeutic potential of MEL-based PCa treatment strategies.
    Keywords:  MCM5; ferroptosis; liquid–liquid phase separation; melatonin; prostate cancer
    DOI:  https://doi.org/10.1111/jpi.70094
  6. J Xenobiot. 2025 Oct 09. pii: 161. [Epub ahead of print]15(5):
    The Antiproliferative Activity of Tatridin A Against Prostate Cancer Cells Is Lost in Acid Medium by Transformation to Desacetyl-β-Cyclopyrethrosin.
    Cecilia Villegas, Rebeca Pérez, Camilo Céspedes-Méndez, Viviana Burgos, Ricardo Baggio, Sebastián Suárez, Bernd Schmidt, Cristian Paz.
      Background: Prostate cancer (PC) progression is strongly driven by dysregulated signaling pathways, with NF-κB playing a central role. Sesquiterpene lactones have been reported to modulate this pathway. This study evaluated and compared the cytotoxic effects of two structurally distinct sesquiterpene lactones: Tatridin A, a germacranolide, and desacetyl-β-cyclopyrethrosin, a eudesmanolide derivative. Their mechanisms of action were also examined, focusing on oxidative stress induction and NF-κB modulation. Methods: Chemical structures were confirmed by NMR and X-ray crystallography. Cytotoxicity was assessed in DU-145 and 22Rv1 PC cells using real-time cell analysis. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were measured with fluorometric assays. NF-κB activity was determined in THP-1 reporter cells and by Western blot of IκBα phosphorylation. Results: Tatridin A markedly reduced viability, showing lower IC50 values (81.4 ± 2.7 µM in DU-145 and 50.7 ± 1.9 µM in 22Rv1 cells) than desacetyl-β-cyclopyrethrosin (166.9 ± 3.2 µM and 290.3 ± 8.3 µM, respectively). It also inhibited proliferation at markedly lower concentrations, with clonogenic IC50 values of 7.7 µM in DU-145 and 5.24 µM in 22Rv1cells. Both compounds increased ROS, but tatridin A induced earlier and stronger responses and ΔΨm loss. Furthermore, tatridin A more effectively inhibited NF-κB signaling than classical inhibitors. Conclusions: Tatridin A exerts cytotoxic effects through oxidative stress, mitochondrial impairment, and NF-κB inhibition, supporting the therapeutic potential of germacranolides for the treatment of advanced PC.
    Keywords:  NF-κB inhibition; eudesmanolide; germacranolide; prostate cancer; sesquiterpene lactones; tatridin A
    DOI:  https://doi.org/10.3390/jox15050161
  7. Vavilovskii Zhurnal Genet Selektsii. 2025 Oct;29(6): 744-752
    HOXB13 interactome in prostate cancer cells: biochemical and functional interactions between the transcription factors HOXB13 and TBX3.
    М M Erokhin, N Y Kozelchuk, R H Ziganshin, V V Tatarskiy, D A Chetverina.
      Transcription factors represent one of the major groups of proteins, whose suppression leads to tumor growth arrest. Different types of cancer express a specific set of transcription factors that create and maintain unique patterns of gene expression. In prostate cancer cells, one of the key transcriptional regulators is the HOXB13 (Homeobox B13) protein. HOXB13 is known to be an important regulator of embryonic development and terminal cell differentiation. HOXB13 regulates the transcription of many genes in normal and transformed prostate cells and is also capable of acting as a pioneer factor that opens chromatin in the regulatory regions of genes. However, little is known about the protein partners and functions of HOXB13 in prostate cells. In the present study, we searched for protein partners of HOXB13 by immunoaffinity purification followed by high-throughput mass spectrometric analysis (IP/LC-MS) using the PC-3 prostate cancer cell line as a model. The main partners of HOXB13 were found to be transcription factors with different types of DNA-binding domains, including the TBX3, TBX2, ZFHX4, ZFHX3, RUNX1, NFAT5 proteins. Using the DepMap resource, we have shown that one of the identified partners, the TBX3 protein is as critical for the growth and proliferation of prostate cancer cell lines in vitro as HOXB13. Analysis of individual prostate cancer cell lines revealed that knockout of both genes, HOXB13 and TBX3, leads to the death of the same lines: VCaP, LNCaP (clone FGC), PC-3 and 22Rv1. Thus, HOXB13 and TBX3 can be considered together as potential targets for the development of specific inhibitors that suppress prostate cancer cell growth.
    Keywords:  HOXB13; NFAT5; RUNX1; TBX2; TBX3; ZFHX3; ZFHX4; prostate cancer ; regulation of transcription; transcription factors
    DOI:  https://doi.org/10.18699/vjgb-25-82
  8. Clin Cancer Res. 2025 Oct 29.
    Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.
    Michael D Nyquist, Peter Nelson.
      The Androgen Receptor (AR) is the most important therapeutic target for metastatic prostate cancer. Though clinical responses to AR inhibition are nearly universal, so is progression, usually accompanied by reactivation of AR signaling. A new small molecule dual AR degrader/inhibitor shows promise in overcoming resistance and improving clinical outcomes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3045
  9. Biomolecules. 2025 Sep 26. pii: 1369. [Epub ahead of print]15(10):
    Research Advances in Cancer-Associated Fibroblasts in Prostate Cancer Progression.
    Zhonghao Tang, Si Shen, Chenwei Gu, Sixin Li, Yan Qin, Yuanyuan Mi.
      The tumor microenvironment (TME) is crucial for tumor growth and progression, within which cancer-associated fibroblasts (CAFs) play a central role in regulating cancer cell proliferation, metastasis, and therapy resistance through various mechanisms. Although early-stage prostate cancer (PCa) has a high cure rate, advanced disease often becomes difficult to manage due to resistance to standard therapies such as androgen deprivation therapy (ADT). Therefore, a deep understanding of the interaction mechanisms between CAFs and PCa cells is essential for developing novel therapeutic strategies targeting resistant advanced PCa. This review systematically summarizes key signaling pathways and molecular mechanisms through which CAFs promote PCa progression, as recently discovered, evaluates the potential of CAFs as prognostic biomarkers, and discusses novel CAF-based therapeutic targets and intervention strategies for PCa.
    Keywords:  cancer-associated fibroblasts; prostate cancer; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom15101369
  10. J Exp Clin Cancer Res. 2025 Oct 28. 44(1): 296
    Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer.
    Bo Liu, Weiwei Zhang, Yiyi Ji, Jiajin Wu, Ruopeng Su, Xinyu Liu, Ang Li, Kai Shen, Xinyu Chai, Haotian Wu, Zehua Ma, Cong Hu, Zhou Jiang, Liang Dong, Yinjie Zhu, Baijun Dong, Wei Xue, Jiahua Pan, Qi Wang.
       BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with limited therapeutic options. Although cisplatin is recommended as a first-line treatment, its clinical efficacy is hindered by the rapid development of drug resistance, highlighting the urgent need for effective strategies to overcome cisplatin resistance.
    METHODS: We established a NEPC mouse allograft model and performed RNA sequencing to identify genes associated with cisplatin resistance. The role of CCL5 in tumor-stromal crosstalk was investigated using immunofluorescence, ELISA assays, co-culture assays, and CCL5 knockout mice. Mechanistic studies were conducted to explore CCL5/CCR5-mediated signaling pathways. The therapeutic efficacy of cisplatin combined with maraviroc, an FDA-approved CCR5 antagonist, was evaluated in vitro using NEPC cell lines and patient-derived organoids, and in vivo using NEPC mouse models.
    RESULTS: Here, we identify a tumor-stromal interaction mediated by the CCL5/CCR5 axis that drives cisplatin resistance in NEPC. Cisplatin-induced DNA damage promotes a cGAS-STING-dependent senescence program in cancer-associated fibroblasts (CAFs), resulting in the secretion of CCL5, a key senescence-associated secretory phenotype factor. CCL5 from CAFs binds to CCR5 on tumor cells, promoting the formation of a CCR5/β-arrestin1/p85 complex that activates the PI3K/AKT pathway. This activation enhances DNA repair, protecting tumor cells from cisplatin-induced apoptosis. Pharmacologic inhibition of the CCL5/CCR5 pathway using maraviroc, an FDA-approved CCR5 antagonist, sensitizes NEPC cells to cisplatin treatment and significantly prolongs survival in NEPC mouse models.
    CONCLUSIONS: Our findings identify the CCL5/CCR5 axis as a key mediator of tumor-stromal crosstalk driving cisplatin resistance in NEPC. Mechanistically, CAF-derived CCL5 activates AKT signaling in tumor cells by promoting the formation of the CCR5/β-arrestin1/p85 complex. Targeting this pathway with maraviroc in combination with cisplatin offers a promising therapeutic strategy for overcoming drug resistance in NEPC.
    Keywords:  CCL5; Cancer-associated fibroblasts; Cisplatin resistance; Maraviroc; Neuroendocrine prostate cancer
    DOI:  https://doi.org/10.1186/s13046-025-03552-y
  11. Holist Integr Oncol. 2025 ;4(1): 65
    Transcription Factor Dynamics in Neuroendocrine Prostate Cancer Development.
    Yu Wang, Yuzhuo Wang.
      Treatment-induced neuroendocrine prostate cancer (NEPC) represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition, posing a significant clinical challenge. In a recent landmark study, Wang et al. introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor (TF) landscape in prostate cancer progression, uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages. Notably, the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation, dormancy, and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance. This commentary critically evaluates the methodological advancements, the functional significance of the identified TF signatures, and the broader implications of these findings for developing novel therapeutic strategies. By delineating the molecular events driving the transition from androgen receptor (AR)-dependent adenocarcinoma to treatment-resistant NEPC, this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.
    Keywords:  Lineage plasticity; Neuroendocrine prostate cancer (NEPC); Prostate cancer; Three-phase hypothesis; Transcription factors; Tumor dormancy
    DOI:  https://doi.org/10.1007/s44178-025-00197-x
  12. Mol Cancer. 2025 Oct 30. 24(1): 273
    Targeting CXCR2 in prostate cancer cells can block CD47-SIRPα interaction and reverse M2 macrophage polarization in the TME.
    Yi Sun, Shangqing Ren, Wei Wen, Jun Jing, Xu Luo, Shuai Shao, Ruiqi Duan, Guohua Zeng, Ju Guo.
      Neuroendocrine prostate cancer (NEPC) exhibits strong immune evasion and plays a critical role in regulating metabolic reprogramming within prostate cancer. High infiltration of CD36 + M2 tumour-associated macrophages (TAMs) and elevated CD47 expression in NEPC cells are often associated with poor progression-free survival in cancer patients. Understanding the mechanisms that regulate CD36 + M2 TAM infiltration and high CD47 expression in tumour cells within the prostate cancer tumour microenvironment (TME) is essential. Using cell models and two animal models, we discovered that the IL-8/CXCR2 pathway increases acetyl-CoA levels through metabolic reprogramming, which subsequently increases CD47 expression via acetylation. Moreover, this pathway modulates the membrane localization of CD47 by stimulating tumour cells to secrete palmitic acid and utilize palmitoylation mechanisms, thereby protecting tumour cells from macrophage-mediated phagocytosis. The IL-8/CXCR2 pathway also reshapes the metabolic microenvironment of the TME, increasing the infiltration of ω-3/6 polyunsaturated fatty acids (PUFAs) in the TME, which promotes the recruitment of CD36 + M2 TAMs. Preclinical studies in both NSG and C57BL/6 animal models demonstrated that targeting CXCR2 restored TAM phagocytic activity and significantly reduced tumour growth. These findings suggest that CXCR2-targeted immunotherapy holds promising therapeutic potential for prostate cancer and underscores its importance in translational medicine.
    Keywords:  CD36; CD47; IL-8/CXCR2; Lipid metabolism; Macrophage; Prostate cancer
    DOI:  https://doi.org/10.1186/s12943-025-02436-1
  13. Front Oncol. 2025 ;15 1685758
    Anti-neoplastic effects of the antipsychotic drug penfluridol in preclinical prostate cancer models.
    Arjanneke F van de Merbel, Maaike H van der Mark, Tilly Aalders, Martin Puhr, Niven Mehra, Jack Schalken, Geertje van der Horst, Gabri van der Pluijm.
       Introduction: The development of therapy resistance and the formation of distant metastases represent clinical unmet needs for patients with advanced prostate cancer (PCa). The use of drugs for other indications, i.e. drug repurposing, shows great promise for cancer treatment. Drug repurposing could allow new cancer treatments to be introduced relatively quickly and at lower costs. Penfluridol, an approved antipsychotic drug, has strong cytolytic effects in multiple cancers.
    Methods: In this study, we have investigated the potential anti-tumor effects of penfluridol in preclinical and 'near-patient' PCa models.
    Results: Penfluridol significantly reduced the viability of a panel of human PCa cells, induced apoptosis by increasing caspase-3/7 levels and decreased the number of PCa stem cells in vitro. Penfluridol reduced the viability and induced cytotoxic effects in three-dimensional cultures and in ex vivo cultured PCa tissue slices (patient-derived xenograft, freshly isolated PCa biopsies). Moreover, penfluridol significantly reduced the viability of docetaxel-resistant PCa cells and exerted synergistic effects in combination with docetaxel in docetaxel-resistant PCa.
    Discussion: In conclusion, penfluridol exhibited cytotoxic effects in multiple preclinical PCa models. Further research is warranted to address the translational value of our findings.
    Keywords:  cancer stem cells; drug repositioning; drug repurposing; penfluridol; preclinical models; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1685758
  14. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 929-939
    Global Profiling of Lysine Lactylation in Prostate Cancer Cells.
    Jae Yong Kim, Hyunchae Sim, Ann-Yae Na, So Young Choi, Sangkyu Lee.
       BACKGROUND/AIM: Lysine lactylation (Kla) is a recently identified post-translational modification derived from lactate that regulates diverse biological processes. Although Kla has been studied in several cancers, its role in prostate cancer (PC) remains unclear. The objective of this study is to profile Kla in PC in order to explore the mechanisms involved in PC progression.
    MATERIALS AND METHODS: We performed global Kla profiling in PC-3M prostate cancer cells using affinity enrichment with anti-Kla antibodies, followed by LC-MS/MS. Bioinformatics analyses were conducted to explore the functional roles of Kla-modified proteins.
    RESULTS: We identified 681 Kla sites across 379 proteins, with modifications predominantly located in nuclear and cytoplasmic proteins. Enrichment analysis indicated Kla involvement in mRNA splicing, chromatin organization, and glycolysis/gluconeogenesis. Several multifunctional proteins, including AHNAK and nucleolin (NCL) harbor multiple Kla sites. Motif analysis indicated conserved amino acid patterns surrounding Kla sites. Notably, PC-3M cells showed reduced expression of sirtuin (SIRT)3, SIRT5, and SIRT6, which may underlie elevated Kla levels.
    CONCLUSION: This study presents the first comprehensive Kla landscape in PCa, suggesting its potential regulatory role in tumor progression. These findings provide a valuable resource for future studies and support Kla as a possible target for therapeutic intervention in prostate cancer.
    Keywords:  Global lactylome; lysine lactylation; prostate cancer cells; protein modification
    DOI:  https://doi.org/10.21873/cgp.20547
  15. Mol Biol Rep. 2025 Oct 30. 53(1): 31
    HER2 as a molecular trojan horse in prostate cancer: mechanistic insights and therapeutic unlocks.
    Anirban Goutam Mukherjee, Abilash Valsala Gopalakrishnan.
      Human epidermal growth factor receptor 2 (HER2/ERBB2) is a well-established therapeutic target in breast and gastric cancers, but its relevance in prostate cancer (PC) remains unresolved. Although HER2 gene amplification is relatively uncommon in PC, heterogeneous overexpression has been observed, particularly in advanced and castration-resistant PC (CRPC), where it is frequently associated with aggressive clinicopathological features. Experimental studies portray HER2 as a signaling hub, mediating crosstalk with androgen receptor (AR) signaling to sustain tumor growth under androgen-deprived conditions. Concurrent activation of the HER2-PI3K-AKT axis further promotes cell survival, proliferation, and therapeutic adaptation. Moreover, HER2 cooperates with epidermal growth factor receptor (EGFR) and NF-κB pathways, reinforcing tumor plasticity and resistance mechanisms. Despite these compelling biological insights, clinical translation has been disappointing. Early trials with Trastuzumab, Lapatinib, and Pertuzumab yielded minimal benefit, underscoring patient heterogeneity, pathway redundancy, and the lack of biomarker-guided stratification. Lessons from these failures highlight the need for precision oncology approaches that integrate molecular profiling and rational therapeutic combinations. Recent advances, including next-generation HER2-targeted antibody-drug conjugates, bispecific antibodies, and CAR-T cell therapies, as well as strategies combining HER2 inhibition with AR signaling blockade, PI3K/AKT inhibitors, or immunotherapy, offer renewed promise. HER2 in PC thus represents a paradox: biologically significant but clinically underexploited. Reframing HER2 within the AR-PI3K signaling network and leveraging biomarker-driven strategies may finally unlock its therapeutic potential. This review critically examines HER2 in PC, analyzing its mechanistic roles, therapeutic potential, and the challenges that shape its value as both a prognostic biomarker and actionable target.
    Keywords:  Androgen receptor; HER2; PI3K/AKT pathway; Prostate cancer; Therapeutic resistance
    DOI:  https://doi.org/10.1007/s11033-025-11202-x
  16. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 940-952
    Lipid Metabolic Reprogramming During Progression to Castration-resistant Prostate Cancer Identified by Quantitative Proteomics.
    Hyunchae Sim, Subin Bae, Chai Won Park, So Young Choi, Kwang-Hyeon Liu, Eun Hye Lee, Bum Soo Kim, Jae-Wook Chung, Yun-Sok Ha, Jun Nyung Lee, Wonhwa Lee, Tae Gyun Kwon, Sangkyu Lee.
       BACKGROUND/AIM: The progression of hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC) as a result of resistance to androgen deprivation therapy (ADT) remains a major challenge in prostate cancer treatment.
    MATERIALS AND METHODS: To explore the underlying mechanisms, we performed deep comparative proteomic profiling of HSPC and CRPC cell lines. LNCaP and C4-2 cell lines were cultured in isotopically labeled medium, combined, and digested, followed by liquid chromatography-mass spectrometry (LC-MS/MS) and bioinformatic analyses.
    RESULTS: Using SILAC-based proteomic analysis, 3,578 proteins were identified, with 2,474 quantified. In C4-2 cells, 41 proteins were significantly up-regulated, while 201 were down-regulated (fold-change >1.5 or <1.5-1, p<0.05). KEGG pathway analysis linked the increased proteins to fatty acid metabolism and biosynthesis of unsaturated fatty acids. Lipidomic analysis showed a significant rise in fatty acids like DHA, palmitic acid, stearic acid, and arachidic acid, aligning with the proteomic findings.
    CONCLUSION: These results suggest that fatty acids play a key role in HSPC's progression to CRPC, possibly indicating that CRPC cells themselves may generate fatty acids.
    Keywords:  Prostate cancer; castration-resistant prostate cancer; lipid metabolism; proteomics
    DOI:  https://doi.org/10.21873/cgp.20548
  17. J Transl Med. 2025 Oct 29. 23(1): 1189
    Mechanistic insights into SLAMF8-mediated prostate cancer metastasis via the TLR4-NF-κB pathway.
    Qiang Su, Zhao Li, Ning Zhang, Wei Mu, Yi Hu, Bin Dai.
       BACKGROUND: SLAMF8 functions as a cancer-promoting immune checkpoint and could be targeted for therapy in multiple cancer types. Its effect on the immune microenvironment and metastasis of prostate cancer (PCa) is not well understood.
    METHOD: We analyzed SLAMF8 distribution in PCa and normal tissues using TIMER and examined its role in drug sensitivity and immunotherapy for PCa. The prognostic value and clinical relevance of SLAMF8 in PCa were assessed using multiple datasets. GO, KEGG, and GSEA analyses identified dysregulated pathways in tumors with varying SLAMF8 levels. Tumor purity and immune cell infiltration, and their correlation with SLAMF8 overexpression, were analyzed and confirmed in PCa samples. Additionally, CCK-8, flow cytometry, and transwell assays evaluated the viability, apoptosis, and invasion capacity of SLAMF8-overexpressing PCa cells. Allograft models in C57BL/6 mice were used to study the effects of SLAMF8 overexpression on tumor growth and immune cell infiltration.
    RESULTS: Compared to non-tumor tissues, SLAMF8 was overexpressed in PCa tumors. High SLAMF8 levels are linked to poor distant metastasis-free survival (DMFS), higher Gleason scores (GS), and advanced T stage. SLAMF8 expression in PCa tumors negatively correlates with tumor purity but positively correlates with the infiltration of B cells, T cells, dendritic cells, and macrophages. SLAMF8 overexpression in prostate cancer cells promoted cell growth, lowered apoptosis rates, and boosted invasion in vitro, alongside hastening tumor development in mice. This study demonstrates that SLAMF8 enhances PCa metastasis via the TLR4-NF-κB pathway. SLAMF8 is a potential predictor of distant metastasis and a promising target for PCa immunotherapy.
    Keywords:  Immune checkpoint; Metastasis; Prostate cancer; SLAMF8; TLR4-NF-κB pathway
    DOI:  https://doi.org/10.1186/s12967-025-07234-3
  18. BMJ. 2025 Oct 27. 391 r2254
    Prostate cancer drug: NICE approves better tolerated combination for advanced cases.
    Jacqui Wise.
      
    DOI:  https://doi.org/10.1136/bmj.r2254
  19. Comput Biol Chem. 2025 Oct 04. pii: S1476-9271(25)00370-6. [Epub ahead of print]120(Pt 2): 108709
    Computational discovery of resiniferatoxin and euphol as potential androgen receptor inhibitors for prostate cancer therapy.
    Abderrahim Ait Ouchaoui, Salah Eddine El Hadad, El Mehdi Bouricha, Saber Boutayeb, Lahcen Belyamani, Ilhame Bourais.
      Prostate cancer is one of the most common malignancies in men worldwide and is driven in large part by aberrant androgen receptor (AR) signaling. Upon sufficient androgenic concentration, the AR undergoes conformational changes and translocates to the nucleus, where it promotes the transcription of genes essential for tumor growth and progression. In this study, we performed a structure-based virtual screening of 34 phytochemicals from Euphorbia resinifera against the crystal structure of the AR ligand-binding domain (PDB ID: 1E3G). This screening identified two leading compounds, Resiniferatoxin and Euphol, both demonstrated favorable binding poses and docking scores of -10 kcal/mol and -8.6 kcal/mol, respectively, surpassing Flutamide, the standard antiandrogen (-7.7 kcal/mol). Furthermore, a 100 ns molecular dynamics simulation showed that these two molecules formed stable complexes with AR, suggesting their potential utility as natural AR inhibitors in prostate cancer therapy. However, additional experimental studies are essential to validate their efficacy, elucidate their mechanisms of action, and assess their safety profiles, potentially paving the way for innovative plant-based treatments targeting AR-driven prostate cancer.
    Keywords:  Androgen receptor; Euphol; Euphorbia resinifera; Molecular Docking; Molecular Dynamics Simulations; Phytocompounds; Prostate cancer; Resiniferatoxin
    DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108709
  20. Photochem Photobiol Sci. 2025 Oct 27.
    Antitumor, biological and nonlinear optical activities of novel thiazolidines.
    Sabah Abbas, Ahmed A Majed, Mostafa Hashim Moker, Tahseen A Alsalim, Toufik Bensafi, Djebar Hadji, Benamar Baroudi, Ahmed Adnan Al-Khafagi, Dawood S Abid.
      The novel series of 3-acetyl phenylthiazolidine-4-carboxyamide derivatives were prepared, structurally characterized by FTIR, 1H and 13C-NMR, and mass spectrometry, and described for their possible applications against prostate cancer cells. These amide thiazolidines include many substituents on a phenyl ring, such as 3-NO2, 3,4,5-tri-OCH3, 4-COCH3, 3,4-di-OCH3, benzoyl, and diphenyl. Biological activity assays applying the MTT assay for PC3 cells were shown to evaluate the bioactivity of these thiazolidines. The amide thiazolidines revealed promising cytotoxic amide thiazolidines TAM1 (IC50 = 75.95 µg/ml) and TAM2 (IC50 = 79.82 µg/ml) displayed notable strength against PC3 cells. The molecular docking against DNA gyrase, two types of proteins (1SJO and 4HJO), and enzymes exposed strong binding interactions of an examined molecule inside their active sites, making them valuable applicants for further development as therapeutic agents against the human prostate cancer cell line (PC3). Strong total first hyperpolarizability βtot up to 2766.67 a.u. has been achieved for TAM1. The direct correlation was attained between the total hyperpolarizability βtot and Eg (energy gap) and between a βHRS and β//. This study will offer additional knowledge regarding exploring novel thiazolidines, revealing promising, cytotoxic, and nonlinear optical thiazolidines, and progressing in technologies that manipulate and control light for various purposes, such as optical signal processing, photorefractive devices, and photonics.
    Keywords:  Amide; Molecular docking; Nonlinear optics; Prostate cancer; Thiazolidine
    DOI:  https://doi.org/10.1007/s43630-025-00800-0
  21. Mater Today Bio. 2025 Dec;35 102374
    3-acetyl-11-keto-β-boswellic acid and chitosan-Ag nanoparticles for synergistic tumor-resident bacteria mediated prostate cancer therapy.
    Bo Zou, Xuefei Tian, Ruisong Gao, Hongping Long, Yan Long, Bin Liu, Qing Zhou.
      Intratumoral bacteria play a critical role in prostate cancer (PCa) progression by altering the tumor microenvironment. Modulating these bacterial populations can significantly enhance the effectiveness of cancer therapies, including chemotherapy and immunotherapy. However, the use of antibiotics often yields inconsistent results due to poor targeting and the potential for bacterial resistance. In this study, we propose a novel therapeutic approach combining 3-acetyl-11-keto-β-boswellic acid (AKBA) with chitosan-coated silver nanoparticles (Chi-Ag NPs) to enhance PCa treatment efficacy by eliminating tumor-resident bacteria and inhibiting tumor invasion and metastasis. To address the challenge of drug targeting in vivo, we designed nanocomposites (SZTI01@Chi-Ag@PLGA@AKBA) that specifically target prostate-specific membrane antigen (PSMA) receptors on PCa cells. Compared to free drugs, SZTI01@APA NPs showed a 1.67-fold increase in accumulation at the tumor site. Once localized, the AKBA and Chi-Ag NP combination effectively inhibited tumor proliferation, induced apoptosis, and eliminated tumor-resident bacteria. Additionally, the nanocomposites suppressed Th17 cell infiltration and reduced IL-17 secretion, thereby inhibiting primary tumor growth and metastasis. In summary, this bacteria-targeting strategy enhances chemotherapy efficacy and immune responses, presenting a promising therapeutic approach for improving PCa treatment outcomes and advancing the development of more effective therapies.
    Keywords:  3-acetyl-11-keto-β-boswellic acid; Chi-Ag NPs; Prostate cancer; Tumor-resident bacteria
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102374
  22. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 953-970
    SCAMP3 and EPS8 Cooperatively Regulate EGFR Signaling to Promote Enzalutamide Resistance and Metastatic Potential in Prostate Cancer.
    Wei-Lun Huang, Pei-Fang Hsieh, Sih-Han Chen, Richard Chen-Yu Wu, Hsing-Cha Mai, Chun-Hsien Wu, See-Tong Pang, Yu-Lin Yang, Victor Chia-Hsiang Lin.
       BACKGROUND/AIM: Prostate cancer is the second most common malignancy among men worldwide, with progression to castration-resistant prostate cancer (CRPC) posing significant therapeutic challenges. Enzalutamide, a second-generation androgen receptor antagonist, initially demonstrates efficacy in treating metastatic CRPC; however, resistance inevitably develops. Dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway has been implicated in therapy resistance and metastatic progression. Secretory carrier membrane protein 3 (SCAMP3) and epidermal growth factor receptor substrate 8 (EPS8) are known regulators of EGFR trafficking and signaling. This study aimed to investigate their cooperative roles in enzalutamide-resistant prostate cancer cells.
    MATERIALS AND METHODS: LNCap prostate cancer cells and their enzalutamide-resistant derivatives (LNCap-Enz) were treated with 100 ng/ml epidermal growth factor (EGF). Protein expression and interactions were analyzed by Western blotting and co-immunoprecipitation. SCAMP3 and EPS8 were knocked down using shRNA technology, while complementary overexpression studies were conducted using pcDNA-SCAMP3 and pcDNA-EPS8 vectors. Effects on EGF receptor (EGFR) expression and downstream signaling molecules (STAT3, AKT, ERK) were evaluated in both loss-of-function and gain-of-function models.
    RESULTS: EGF stimulation enhanced the expression of EGFR, SCAMP3, and EPS8 in both LNCap and LNCap-Enz cells while promoting formation of a protein complex involving these proteins and the androgen receptor (AR-V7). Knockdown of SCAMP3 or EPS8 reduced EGFR expression and attenuated STAT3, AKT, and ERK activation. Conversely, overexpression of SCAMP3 or EPS8 increased EGFR levels and enhanced downstream signaling activation. These bidirectional effects highlight the functional interdependence between SCAMP3 and EPS8 in regulating EGFR stability and signaling.
    CONCLUSION: SCAMP3 and EPS8 cooperatively maintain EGFR stability and signaling in prostate cancer cells, playing a critical role in enzalutamide resistance and metastatic progression. Targeting the SCAMP3-EPS8-EGFR axis offers promising therapeutic opportunities for advanced prostate cancer.
    Keywords:  EGFR signaling; EPS8; Prostate cancer; SCAMP3; drug resistance; enzalutamide resistance; metastasis
    DOI:  https://doi.org/10.21873/cgp.20549
  23. Int J Mol Sci. 2025 Oct 13. pii: 9969. [Epub ahead of print]26(20):
    Cytotoxicity of Mimusops caffra-Based Ursolic Acid, Oleanolic Acid and Derivatives Against Human Cancerous and Non-Cancerous Cell Lines.
    Sithenkosi Mlala, Opeoluwa Oyehan Oyedeji, Gbemisola Morounke Saibu, Mavuto Gondwe, Adebola Omowunmi Oyedeji.
      According to the World Health Organization, cancer is still the leading cause of death for humans worldwide. Although over 100 chemotherapeutic agents are currently available for the treatment of cancer patients, the overall long term clinical benefit is disappointing due to the lack of effectiveness or severe side effects from these drugs. The use of complementary and alternative medicinal products from plants has continued to increase in past decades, due to fewer side effects of bioactive compounds from medicinal plants of which pentacyclic triterpenoids have been identified as one class of secondary metabolites that could play an important role in the treatment and management of a number of non-communicable diseases. The main aim of this study is to extract, isolate, identify, and elucidate pentacyclic triterpenoid (ursolic acid, UA (1), and oleanolic acid, OA (2)) from Mimusops caffra. Semi-synthesis of UA was carried out to obtain some triterpenoid derivatives (3-O-acetyl ursolic acid, AUA (3), ursolic-28-methylate, UM (4), and 3-acetylursolic-methylate, AUM (5)), and we evaluated these compounds as anti-cancer therapeutic agents. Isolation of ursolic acid (UA) (1) from M. caffra is always accompanied by its isomer oleanolic acid (OA) (2) due to their similar retention factors (Rf) values. Acetylation and deacetylation techniques were used to isolate compounds 1 and 2. In vitro cytotoxicity activities of UA, AUA UM, and AUM were evaluated against various cancer cell lines, such as human breast adenocarcinoma cancer cell lines (MDA), human liver cancer cell lines (HepG2), human prostate cancer cell lines (PC3) and non-cancerous human fibroblast cell lines (KMST-6) using MTT assays. The UM exhibited remarkable cytotoxic activities against cancer cells, while little or no activities were observed on non-cancerous cell lines, which indicates that the addition of methyl at C-28 of UA is essential to enhance its activity as a therapeutic agent for cancer. The AUA showed moderate or no cytotoxicity against the different cancer cell lines, which is less than that of the UA parent compound. Moreover, these results suggest that ursolic acid and UA derivatives are potential therapeutic drugs for human breast, liver, and prostate cancers.
    Keywords:  3-O-acetyl ursolic acid; 3-acetylursolic-methylate; HepG2; KMST-6; MDA; PC3; cancer; cytotoxicity; ursolic acid; ursolic-28-methylate
    DOI:  https://doi.org/10.3390/ijms26209969
  24. Radiol Imaging Cancer. 2025 Nov;7(6): e259030
    Treatment-Response Prediction for Metastatic Castrate-Resistant Prostate Cancer Using PSMA PET.
    Loise Wairiri, Michael R Folkert.
      
    DOI:  https://doi.org/10.1148/rycan.259030
  25. J Hematol Oncol. 2025 Oct 29. 18(1): 95
    PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy.
    Yangli Xu, Duoli Xie, Chunhao Cao, Zhuqian Wang, Yue Ju, Lili Guan, Xuelong Li, Shanshan Wu, Luo Zhang, Chao Liang, Xiushan Yin.
      Although chimeric antigen receptor (CAR)-T cells have demonstrated remarkable efficacy against hematologic malignancies, their effectiveness in solid tumors is limited by poor tumor infiltration and severe cytokine release syndrome (CRS). CAR-macrophage (CAR-M) therapy has emerged as a promising alternative, leveraging the innate tumor-homing capacity of macrophages while enabling antigen-specific phagocytosis and immune activation without triggering CRS. Prostate-specific membrane antigen (PSMA) represents an ideal therapeutic target due to its high expression in prostate cancer cells. In this study, we engineered PSMA-specific CAR-M with potent anti-tumor activity against prostate cancer cells both in vitro and in vivo. PSMA-specific CAR-M exhibited strong antigen-dependent phagocytic capability and underwent polarization toward a pro-inflammatory, tumoricidal phenotype upon PSMA recognition. Mechanistically, interaction with PSMA-expressing prostate cancer cells induced metabolic reprogramming, characterized by enhanced glycolytic activity and suppressed oxidative phosphorylation, which reinforced the anti-tumor function of CAR-M. Our findings highlight PSMA-targeted CAR-M therapy as a promising immunotherapeutic approach for prostate cancer.
    Keywords:  CAR-M; Immunotherapy; Metabolic reprogramming.; PSMA; Prostate cancer
    DOI:  https://doi.org/10.1186/s13045-025-01743-w
  26. Cell Mol Biol Lett. 2025 Oct 28. 30(1): 126
    Circular RNA circSLC39A10 promotes prostate cancer progression by activating Wnt signaling via the miR-936/PROX1/β-catenin axis.
    Kailai Chen, Xiang Pan, Shiheng Zhang, Meiqi Xu, Xi Chen, Feng Pei, Mengyuan Wu, Fanlong Meng, Bin Sun, Manjie Zhang, Yakun Luo.
      Circular RNAs (circRNAs) play a crucial role in the initiation and development of cancers. Understanding circRNAs' functions and molecular mechanisms in tumor development is expected to reveal new diagnostic indicators and therapeutic targets of prostate cancer (PCa). In our study, we identified a new circRNA hsa-circ-0057553 (circSLC39A10) in PCa from a bioinformatic microarray analysis. The levels of circSLC39A10 were observed to be markedly elevated in both prostate cancer cells and tissues. This increased expression was associated with multiple clinicopathological features, suggesting its potential as a new diagnostic indicator for PCa. CircSLC39A10 exhibited oncogenic effects on the proliferation, migration, invasion, and metastasis of prostate cancer cells both in vivo and in vitro. CircSLC39A10 was identified as a factor that promoted the malignant progression of PCa cells through the miR-936/PROX1/β-catenin pathway, ultimately leading to the activation of Wnt signaling. Overall, circSLC39A10 is an oncogenic circRNA with potential as a biomarker for PCa. The identified circSLC39A10/miR-936/PROX1/β-catenin axis shows promise as an innovative therapeutic target for PCa.
    Keywords:  Metastasis; PROX1; Prostate cancer; Wnt/β-catenin; circSLC39A10; miR-936
    DOI:  https://doi.org/10.1186/s11658-025-00814-7
  27. Bioact Mater. 2026 Feb;56 15-32
    Biomimetic bone niche reconstructs proliferation-inhibited and therapy-resistant bone-metastatic prostate cancer.
    Xin Chen, Yujiao Peng, Ying Zhao, Huiling Liu, Qijun Lin, Xihong Fu, Lianheng Chen, Zhongte Peng, Jianfeng Huang, Yu Luo, Xuenong Zou, Lei Yang, Xinsheng Peng, Chun Liu.
      Prostate cancer bone metastases often harbor a rare subset of tumor cells with suppressed proliferation, contributing to therapy resistance and disease relapse. However, the lack of physiologically relevant in vitro models has hindered mechanistic and therapeutic advances. Here, we engineered a 3D bone-like microenvironment by integrating calcium phosphate scaffolds, decellularized extracellular matrix (dECM), mesenchymal stem cells (MSCs), and osteoblasts. This biomimetic niche induced a proliferation-inhibited state in prostate cancer cells, closely mirroring transcriptomic signatures identified from patient-derived single-cell RNA sequencing datasets. Tumor cells in this niche also displayed enzalutamide resistance, accompanied by metabolic reprogramming and activation of pro-survival signaling. This platform provides a clinically relevant tool for modeling bone metastatic prostate cancer and accelerating the development of therapies targeting resistant tumor states.
    Keywords:  3D bioprinting; Bone microenvironment; Drug resistance; Prostate cancer metastasis; Tumor dormancy
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.09.041
  28. Asian Pac J Cancer Prev. 2025 Oct 01. pii: 91883. [Epub ahead of print]26(10): 3571-3580
    The Association Between Selenium Levels and Risk of Prostate Cancer: A Systematic Review and Meta-analysis of 16,964 Participants (1980-2024).
    Mobin Ghaderi, Farhad Moradpour, Hassan Moaiery, Sina Fattahi, Hojat Dehghanbanadaki, Yousef Moradi.
       BACKGROUND: Numerous studies worldwide have explored the link between selenium levels and prostate cancer, yet their findings remain inconsistent. This systematic review and meta-analysis aimed to clarify this association by synthesizing results from analytical observational studies, including cohort and case-control studies. The insights from this meta-analysis could significantly impact healthcare decisions, clinical management, and treatment guideline updates.
    METHOD: This study utilized a systematic review and meta-analysis approach, conducting a comprehensive literature search across international databases such as PubMed (Medline), Scopus, Web of Science, and Embase with relevant keywords. Articles were screened at the title, abstract, and full-text levels, followed by a quality assessment using the NOS checklist. Statistical analysis was performed using STATA version 17.
    RESULTS: After pooling data from eleven studies investigating the relationship between plasma or serum selenium and prostate cancer risk, findings indicated that higher selenium levels were associated with an 11% reduced risk of prostate cancer (RR= 0.89; 95% CI: 0.83 - 0.95; P-value= 0.03; I square= 34.46%). When selenium dosage was considered, with doses below 70 μg as the reference, individuals exposed to 130-160 μg exhibited a reduced cancer risk of 0.85 (RR= 0.85; 95% CI: 0.76 - 0.96; P-value= 0.18; I square= 27.37%), while those exposed to doses of 160 μg or higher had an RR of 0.89 (95% CI: 0.69 - 1.15; P-value= 0.19; I square= 0.00%). Additionally, an inverse relationship was found between selenium levels in toenails and prostate cancer risk (RR= 0.61; 95% CI: 0.50 - 0.75; P-value= 0.63; I square= 0.00%) and advanced prostate cancer (RR= 0.73; 95% CI: 0.67 - 0.80; P-value= 0.00; I square= 69.79%).
    CONCLUSION: This meta-analysis suggests that selenium may have a protective effect against prostate cancer. Strategies to optimize selenium intake should be considered for prostate cancer prevention and management.
    Keywords:  Evidence Synthesis; Meta-analysis; Prostate Cancer; Selenium Level
    DOI:  https://doi.org/10.31557/APJCP.2025.26.10.3571
  29. Sci Rep. 2025 Oct 28. 15(1): 37602
    Investigation of importance Raman shifts in liquid biopsy diagnostics of prostate cancer.
    Przemysław Mitura, Wiesław Paja, Paweł Płaza, Radosław Starownik, Iga Kuliniec, Michał Godzisz, Krzysztof Bar, Joanna Depciuch.
      This study investigates the potential of Raman spectroscopy for liquid biopsy in prostate cancer using serum samples. We evaluated four machine learning models and Principal Component Analysis (PCA) to classify prostate cancer based on Raman data. Support Vector Machine (SVM) demonstrated the best performance, achieving high accuracy, sensitivity, and F1 scores, with the highest overall. Random Forest (RF) also showed strong results, with accuracy of 0.87. The analysis identified two key spectral bands: 1306 cm-1 and 2929 cm-1, as potential biomarkers for prostate cancer. The PCA revealed that particular it is possible to differentiate serum collected from control and prostate cancer patients. Correlation analysis showed that the 2929 cm-1 band was significantly associated with PSA levels, MRI PIRADS, and lymph node metastasis (pN+), while the 1306 cm-1 band showed strong correlation with PSA and MRI PIRADS. These findings suggest that Raman spectroscopy, particularly the 2929 cm-1 band, holds promise as a reliable method for prostate cancer detection in liquid biopsy applications.
    Keywords:  Marker; Prostate cancer; Raman spectroscopy; Serum
    DOI:  https://doi.org/10.1038/s41598-025-21204-1
  30. Biomedicines. 2025 Oct 07. pii: 2442. [Epub ahead of print]13(10):
    Cyclophilin Inhibitor Rencofilstat Combined with Proteasome Inhibitor Ixazomib Increases Proteotoxic Cell Death in Advanced Prostate Cancer Cells with Minimal Effects on Non-Cancer Cells.
    Carlos Perez-Stable, Alicia de Las Pozas, Medhi Wangpaichitr, Robert T Foster, Daren R Ure.
      Background/Objective: Proteotoxic stress induced by inhibitors of the ubiquitin-proteasome system has been successful in multiple myeloma but not in solid cancers such as prostate cancer. Our objective is to find a combination with proteasome inhibitors that increases apoptotic cell death in all types of prostate cancer without harming non-cancer cells. Methods: The effectiveness of rencofilstat, a pan-cyclophilin inhibitor, combined with the ixazomib proteasome inhibitor, was investigated in multiple prostate cancer and non-cancer cells. Inducible knockdown of stress response XBP1s and cyclophilins A/B and inducible expression of XBP1s and cyclophilin B were developed in prostate cancer to determine functional roles. Results: Rencofilstat + ixazomib increased apoptotic cell death in prostate cancer but not in non-cancer cells. We investigated the effects on XBP1s and PERK, important unfolded protein response factors required for cells to survive proteotoxic stress. The results revealed that XBP1s had a pro-survival role early, but maintenance at later times of rencofilstat + ixazomib treatment resulted in cell death. In addition, decreased PERK and phospho-eIF2α likely maintained protein synthesis to further enhance proteotoxic stress. In contrast, rencofilstat + ixazomib did not alter XBP1s or PERK in non-cancer cells. Additional genetic experiments showed that the RCF targets cyclophilins A, B, and D had protective effects. Rencofilstat increased extracellular secretion of cyclophilin B, but rencofilstat + ixazomib reduced glycosylation and, likely, the biological function of CD147 (CypB receptor) and decreased downstream ERK signaling. Conclusions: Rencofilstat + ixazomib may be a new strategy for increasing proteotoxic stress and apoptotic cell death in advanced prostate cancer cells with less toxic side effects.
    Keywords:  PERK; XBP1s; apoptosis; cyclophilin; proteasome; unfolded protein response
    DOI:  https://doi.org/10.3390/biomedicines13102442
  31. Semin Oncol. 2025 Oct 24. pii: S0093-7754(25)00117-4. [Epub ahead of print]53(1): 152425
    The nervous system in prostate cancer: A basic science and clinical perspective.
    Dawid Sigorski, Anna Kasprzyk-Pawelec, Maciej Michalak, Roman Sosnowski, Michał M Hryciuk, Aleksandra Sejda, Jacek Gulczyński, Joanna Kitlinska, Sergiusz Nawrocki, Ewa Iżycka-Świeszewska.
      Prostate cancer (PCa) constitutes an important health challenge worldwide. The nervous system, in a complex and multimodal manner, regulates prostate physiology and PCa development and affects the course of the disease. The phenomena of axonogenesis and neurogenesis, first described in PCa, were a breakthrough discovery that changed our understanding of cancer-nerve crosstalk. Different nerve types within the cancer stroma and tumor surroundings create complex interactions between the cancer microenvironment elements based on neurotransmission, affecting the hallmarks of cancer. The most common form of PCa and nerve interaction is the perineural invasion (PNI), which recently has been suggested as a driver of metastases. Additionally, many preclinical discoveries depict the molecular mechanisms of altered nerve activity, showing the pivotal role of sympathetic and parasympathetic signaling systems in localized and advanced PCa, axon-guidance molecules and neurotrophin. The neuroendocrine switch in advanced PCa is one of reasons of lethal, castration-resistant phase of the disease. Knowledge about the infiltration status of the periprostatic nerves present in radiological imaging is important for urologists in planning the treatment. Although some studies suggest that PNI and nerve density may be prognostic factors in PCa, it is necessary to evaluate these indicators better and apply them to practice. The neural-based therapeutic application in PCa is limited currently. Some studies showed that β blockers reduce PCa-specific mortality and neuroendocrine differentiation potential. This review provides a comprehensive, up-to date synthesis of PCa neurobiology, uniquely integrating both preclinial and clinical perspectives.
    Keywords:  Axonogenesis; Cancer neuroscience; Nerve density; Nerve-sparing surgery; Neurogenesis; Perineural invasion; Prostate cancer
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152425
  32. Phys Imaging Radiat Oncol. 2025 Oct;36 100850
    Identifying the optimal time point for adaptive re-planning in prostate cancer radiotherapy to minimise rectal toxicity using normal tissue imaging biomarkers.
    Zhuolin Yang, David J Noble, Sarah Elliot, Leila Shelley, Thomas Berger, Raj Jena, Duncan B McLaren, Neil G Burnet, William H Nailon.
       Background and purpose: Adaptive radiotherapy (ART) in prostate cancer (PCa), although not yet standard practice, is typically triggered by inter-fractional anatomical changes that emerge progressively during treatment. This study investigates whether radiomics extracted before and during treatment can identify the optimal time point for re-planning, with the goal of reducing late rectal bleeding.
    Materials and methods: This study included 187 PCa patients from the single-centre, prospectively collected VoxTox dataset (UK-CRN-ID-13716), treated with image-guided radiotherapy using TomoTherapy and daily MVCT. Patients received either 74 Gy in 37 fractions (N = 110) or 60 Gy in 20 fractions (N = 77). Radiomic features were extracted from pre-treatment planning CTs and daily MVCTs. Grade ≥ 1 rectal bleeding was assessed at 2 years post-treatment using CTCAE v4.03. Two analysis strategies were employed: a separate analysis, where weekly features were evaluated independently; and a cumulative analysis, which progressively incorporated features from previous weeks. Logistic regression models with elastic net penalty were trained and evaluated using AUC.
    Results: In both groups, week 1 provided the highest standalone predictive performance (test AUC = 0.766 for 74 Gy; 0.734 for 60 Gy). In the cumulative analysis, week 3 was optimal for the 74 Gy group (test AUC = 0.767), balancing performance and timing. For the 60 Gy group, week 1 remained optimal but suffered from reduced generalisability (test AUC = 0.643).
    Conclusions: Radiomic analysis of daily imaging can support early, proactive ART in PCa, offering a personalised strategy to reduce late rectal bleeding beyond conventional anatomy-based approaches.
    Keywords:  Adaptive radiotherapy; Machine learning; Prostate cancer; Radiomics
    DOI:  https://doi.org/10.1016/j.phro.2025.100850
  33. Urol Case Rep. 2025 Nov;63 103245
    Multidisciplinary therapy targeting histological heterogeneity in prostate cancer with bone marrow carcinomatosis: A case report.
    Naoya Nagaya, Kento Hokota, Kaho Hirose, Junro Yanai, Junki Morino, Yuki Nagashima, Akiko Nakajima, Kazuhiko Fujita, Shigeo Horie.
      Prostate cancer with bone marrow carcinomatosis is rare and has a poor prognosis. A 68-year-old man with severe thrombocytopenia was diagnosed with prostate cancer based on MRI and bone marrow biopsy findings. Initial treatment with a GnRH antagonist and apalutamide showed limited efficacy for thrombocytopenia despite PSA response, prompting the addition of carboplatin and etoposide (CE) chemotherapy. Thrombocytopenia resolved following CE chemotherapy. After four CE cycles, ProGRP stabilized and PSA decreased significantly. Tumor control was maintained for a year with hormonal therapy. This case underscores the need for early, multidisciplinary treatment in histologically heterogeneous prostate cancer.
    DOI:  https://doi.org/10.1016/j.eucr.2025.103245
  34. Curr Issues Mol Biol. 2025 Oct 08. pii: 823. [Epub ahead of print]47(10):
    TMPRSS2 Expression in Lung Tissue of Prostatic Adenocarcinoma Patients: Androgen Deprivation Therapy and Relevance to SARS-CoV-2 Infection.
    Marcela Riveros Angel, David Loeffler, Ahmad Charifa, Ryan B Sinit, Taylor Amery, Beyza Cengiz, Tomasz M Beer, George V Thomas.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is facilitated by transmembrane protease serine 2 (TMPRSS2), which is regulated by the androgen receptor (AR). Androgen deprivation therapy (ADT), widely used in prostate cancer treatment, may potentially modulate TMPRSS2 expression, affecting SARS-CoV-2 infection susceptibility and severity. We evaluated the impact of ADT on pulmonary TMPRSS2 expression in prostate cancer patients and analyzed differences in expression patterns associated with specific ADT regimens. We examined TMPRSS2 immunohistochemical expression in lung tissue from 20 consecutive autopsy cases of men with prostate cancer (6 receiving ADT at time of death), compared with non-ADT prostate cancer patients and age-matched women controls. Histoscores were calculated by assessing the percentage and intensity of pneumocyte TMPRSS2 expression. Prostate cancer patients receiving ADT showed significantly reduced pulmonary TMPRSS2 expression compared to non-ADT patients (mean histoscores: 152.7 vs. 225.0, p = 0.037) and age-matched women controls (mean histoscores: 152.7 vs. 238.0, p = 0.024). Direct AR antagonists (apalutamide, bicalutamide) produced greater TMPRSS2 suppression than Gonadotropin-Releasing Hormone modulators or androgen biosynthesis inhibitors. No significant correlation was observed between the TMPRSS2 expression and Gleason score, PSA levels, or underlying lung pathology. Our findings demonstrate that ADT significantly reduces pulmonary TMPRSS2 expression, with direct AR antagonists showing the strongest effect. This suggests a potential mechanistic explanation for differential COVID-19 susceptibility and provides a rationale for investigating AR-targeted therapies as potential protective interventions against SARS-CoV-2 infection severity.
    Keywords:  SARS-CoV-2; TMPRSS2; androgen deprivation therapy (ADT); androgen receptor (AR); prostate
    DOI:  https://doi.org/10.3390/cimb47100823
  35. Nat Sci Sleep. 2025 ;17 2783-2795
    Association Between Obstructive Sleep Apnea and Prostate Cancer: NHANES and the Mendelian Randomization Study.
    Ying Liu, Binglei Jiang, Long Xia, Erhao Bao, Li Wang, Ping-Yu Zhu.
       Background: Obstructive sleep apnea is a common condition worldwide, and prostate cancer is the most prevalent cancer among men. However, the link between OSA and prostate cancer remains unclear. This study aims to explore the relationship between OSA and prostate cancer.
    Methods: Initially, a multivariable regression analysis was conducted to control for potential confounders and assess the impact of OSA on the risk of developing prostate cancer. Subsequently, age-stratified analyses were performed to further investigate the relationship between OSA and prostate cancer across different age groups. Finally, Mendelian randomization was employed to evaluate the causal relationship between OSA and prostate cancer risk.
    Results: The multivariable regression analysis of the NHANES data showed no significant association between OSA and prostate cancer after controlling for age, smoking habits, hypertension, diabetes, cardiovascular diseases, stroke, alcohol consumption, body mass index (OR = 0.83; 95% CI: 0.46-1.48; p = 0.49). However, age-stratified analysis revealed a significant negative correlation between OSA and prostate cancer in the younger population (<60 years) (OR = 0.07; 95% CI: 0.01-0.74; p = 0.03), whereas no significant association was found in the elderly population (≥60 years) (OR = 1.01; 95% CI: 0.69-1.49; p = 0.96). Finally, our Mendelian randomization results did not find a causal relationship between OSA and prostate cancer (OR = 0.992; 95% CI: 0.876-1.124; p = 0.906).
    Conclusion: The findings indicate that while there is no significant association between OSA and prostate cancer in the overall analysis, a significant negative correlation exists in the younger population. The lack of significant association in the Mendelian randomization analysis may be due to the inability to perform age stratification. Further prospective studies and mechanistic research are needed to better understand the biological mechanisms underlying this association.
    Keywords:  mendelian randomization; national health and nutrition examination survey; obstructive sleep apnea; prostate cancer
    DOI:  https://doi.org/10.2147/NSS.S496540
  36. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 1044-1060
    Verbascoside Suppresses Epithelial-Mesenchymal Transition and Mitochondrial Biogenesis by Targeting Anti-senescence Signaling in Castration-resistant Prostate Cancer.
    Hsing-Chia Mai, Pei-Fang Hsieh, Chun-Hsien Wu, Richard C Wu, Sih-Han Chen, Wei-Lun Huang, Mu-Chiao Tung, Yu-Lin Yang, Victor C Lin, Chiang-Ting Wang.
       BACKGROUND/AIM: Verbascoside, a natural phenylethanoid glycoside, has demonstrated significant therapeutic potential in castration-resistant prostate cancer (CRPC). This study aimed to elucidate the mechanistic pathways through which verbascoside exerts its antisenescence and anti-metastatic effects, focusing on epithelial-mesenchymal transition (EMT), oxidative stress response, and mitochondrial biogenesis regulation in CRPC cells.
    MATERIALS AND METHODS: CRPC cell models were treated under various concentrations of verbascoside. EMT markers, oxidative stress-related proteins, mitochondrial biogenesis regulators, and proinflammatory cytokines were assessed using Western blotting and ELISA. Cellular senescence and proliferation were evaluated through analysis of p38 MAPK activation and key cell cycle regulators (p16, p21, p27, and retinoblastoma protein (Rb).
    RESULTS: Verbascoside treatment inhibited EMT, reduced oxidative stress markers, and enhanced mitochondrial biogenesis, supporting cellular energy homeostasis. It also suppressed the secretion of proinflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1, associated with the senescence-associated secretory phenotype. Downstream signaling analysis revealed that verbascoside decreased p38 MAPK activation and down-regulated p16, p21, p27, and Rb, thereby attenuating prosenescence signaling and proliferation control.
    CONCLUSION: Verbascoside attenuates CRPC progression by modulating EMT, alleviating oxidative damage, enhancing mitochondrial function, and inhibiting prosenescence signaling pathways. These findings highlight its therapeutic potential for targeting senescence-related mechanisms in aggressive prostate cancer and provide a basis for future CRPC management strategies.
    Keywords:  Verbascoside; anti-senescence; castration-resistant prostate cancer; epithelial–mesenchymal transition; mitochondrial biogenesis
    DOI:  https://doi.org/10.21873/cgp.20554
  37. BMC Cancer. 2025 Oct 25. 25(1): 1645
    Assessing the relationship between cardiometabolic diseases and the risk of developing aggressive prostate cancer: a systematic review and meta-analysis.
    Aurmin J Amirmokri, Christopher A Loffredo, Kepher H Makambi, Nancy A Dawson.
       BACKGROUND: Prostate cancer is the most prevalent cancer among men within the U.S. and globally, with rising incidence, including advanced-staged disease. Risk factors for aggressive prostate cancer are not well defined. This systematic review and meta-analysis provide an overview of the relationship between cardiometabolic diseases (diabetes, dyslipidemia, obesity, and hypertension) and aggressive prostate cancer.
    METHODS: Aggressive prostate cancer was defined as disease that has spread or is at high risk of spreading: high-risk or very high-risk localized (T3-T4, Grade Group 4-5), node-positive (N1), or metastatic (M1). Using PRISMA guidelines, a total of 4,830 publications revealed 25 cohort studies of over 974,000 men. Following the systematic review of these prospective studies of men with prostate cancer, R was utilized to run a random effects model, yielding hazard ratios with 95% confidence intervals and generating forest plots with measures of heterogeneity.
    RESULTS: Examination of these studies revealed that a positive association exists. Diabetes was associated with a significantly increased risk of aggressive prostate cancer (HR = 1.18; 95% CI: 1.07-1.30; p = 0.0008). Obesity also showed a significant association (HR = 1.15; 95% CI: 1.06-1.24; p = 0.0006), as did hypertension, though to a lesser degree (HR = 1.07; 95% CI: 1.00-1.14; p = 0.04). Dyslipidemia was not significantly associated with aggressive prostate cancer (HR = 1.03; 95% CI: 0.98-1.03; p = 0.26).
    DISCUSSION: Three of the four cardiometabolic disease components (diabetes, obesity and hypertension) were shown to have statistical significance and offered intriguing evidence on their potential associations with aggressive prostate cancer. Dyslipidemia's association was not statistically significant, which could be attributed to variations in methods of assessment and differing mechanistic effects. High heterogeneity and limited study availability remain key limitations.
    CONCLUSION: If such associations between cardiometabolic diseases and prostate cancer aggressiveness are shown to be cause and effect, such controllable and treatable conditions can allow oncologists to work alongside primary care physicians to improve patient outcomes and reduce the incidence of aggressive disease. Through the promotion of lifestyle modifications, tighter cardiometabolic control, and targeted interventions, public health efforts might improve prostate cancer outcomes.
    Keywords:  Cohort studies; Diabetes mellitus; Dyslipidemias; Hypertension; Metastasis; Obesity; Prostate cancer; Systematic review and meta-analysis
    DOI:  https://doi.org/10.1186/s12885-025-14809-2
  38. ChemMedChem. 2025 Oct 31. e202500682
    Profiling Inhibitor Scaffolds for the Cancer Target Jumonji-C Domain-Containing Protein 6.
    Thomas P Corner, Eidarus Salah, Anthony Tumber, James P Holt-Martyn, Lennart Brewitz, Christopher J Schofield.
      The human 2-oxoglutarate-dependent oxygenase Jumonji-C domain-containing protein 6 (JMJD6) catalyzes post-translational C-5 lysyl residue hydroxylation in multiple proteins. Aberrant JMJD6 catalysis is associated with the upregulation of androgen receptor splice variant 7 (AR-V7), which confers resistance towards antiandrogens used for prostate cancer treatment; JMJD6 is thus a promising cancer target. To date, few small-molecule JMJD6 inhibitors are reported, likely in part reflecting a lack of robust assays to monitor effects of small molecules on catalysis by isolated JMJD6. The use of solid-phase extraction coupled to mass spectrometry assays is described to screen scaffolds for the development of selective JMJD6 inhibitors. The results reveal that the reported JMJD6 inhibitors WL12, SKLB325, and Compound 7p manifest relatively inefficient JMJD6 inhibition in vitro. By contrast, some, but not all, clinically used inhibitors of the human hypoxia-inducible factor-α prolyl hydroxylase domain-containing proteins (PHDs) efficiently inhibit isolated JMJD6, in particular Enarodustat and Desidustat. The results identify attractive scaffolds for the development of selective, cell permeable JMJD6 inhibitors and suggest that JMJD6 inhibition is a potential off-target effect of PHD inhibitors in clinical use.
    Keywords:   2‐oxoglutarate/α‐ketoglutarate‐dependent oxygenase; Desidustat; Enarodustat; JmjC hydroxylase inhibition; Jumonji‐C domain‐containing protein 6; bromodomain‐containing protein 4; high‐throughput inhibition assays; inhibitor discovery; metastatic castration‐resistant prostate cancer
    DOI:  https://doi.org/10.1002/cmdc.202500682
  39. Int J Mol Sci. 2025 Oct 20. pii: 10202. [Epub ahead of print]26(20):
    Are pNF-H, IL-6, BDNF, and NSP Reliable Biomarkers of Cognitive Function in Prostate Cancer Patients?
    Alicja Popiołek, Bartosz Brzoszczyk, Alina Borkowska, Piotr Jarzemski, Mariusz Kozakiewicz, Adam Szelągowski, Maciej Bieliński.
      Cognitive decline can result from various factors, including direct neurotoxic injury, brain tissue damage, inflammation, and disruptions in coagulation and fibrinolysis. This study aimed to examine the relationship between biochemical markers associated with cognitive function and cognitive performance in men with prostate cancer (PC) following radical prostatectomy. Participants underwent a comprehensive evaluation, including clinical assessments (demographic information, medical history, PC progression, and complications such as erectile dysfunction [IIEF-5] and urinary incontinence [ICIQ-UI]), biochemical testing (testosterone, prostate-specific antigen, phosphorylated neurofilament heavy chain [pNF-H], brain-derived neurotrophic factor [BDNF], neuroserpin [NSP], and interleukin-6 [IL-6]), and neuropsychological assessment of cognitive functions. Statistical analysis revealed significant positive correlations between BDNF and NSP levels and performance on delayed memory tasks, specifically the number of correct responses. No other significant associations were found between protein biomarkers and cognitive test outcomes. These findings suggest that the relationship between biochemical markers and cognitive function is complex. However, BDNF and NSP may serve as potential biomarkers for delayed memory impairment in men post-prostatectomy.
    Keywords:  BDNF; Il-6; NSP; biochemical markers; cognitive function; pNF-H; prostate cancer
    DOI:  https://doi.org/10.3390/ijms262010202
  40. J Pharmacol Exp Ther. 2025 Oct 09. pii: S0022-3565(25)40252-3. [Epub ahead of print]392(11): 103739
    Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.
    Dalal Dawud, Malvina Kartamyshev, Tanya Kumar, Uzair M Bilal, Lin Kang, Zakaria Y Abd Elmageed.
      Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge in the treatment of advanced-stage prostate cancer, particularly among American men. Despite current therapeutic options, disease progression and resistance continue to limit patient outcomes. Therefore, the exploration of novel therapeutic strategies is urgently needed. This study investigates the anticancer potential of cambinol, a selective inhibitor of neutral sphingomyelinase 2, alone and in combination with apalutamide, in mCRPC cells. mCRPC cells were treated with different concentrations of cambinol and apalutamide. Cell viability assay was performed to determine the half-maximal inhibitory concentration for each drug. The effects of cambinol on colony formation and cell migration were assessed. Protein expression levels of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin signaling components were evaluated using immunoblotting analysis. Cambinol treatment at 0.1× and 0.5× half-maximal inhibitory concentration significantly reduced cell viability and colony formation in a dose-dependent manner, underscoring its antiproliferative potential. Combined treatment with cambinol and apalutamide led to a marked decrease in cell migration, suggesting synergistic effects in limiting metastatic behavior. Western blot analysis revealed the downregulation of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin, indicating suppression of key survival and proliferation pathways. This study provides new insights into the multifaceted anticancer effects of cambinol in mCRPC cells, including inhibition of cell viability, colony formation, and migration. The observed molecular changes support its role in modulating critical signaling pathways. These findings warrant further investigation into the therapeutic potential of cambinol, both as a monotherapy and in combination with standard therapies, for the treatment of mCRPC. SIGNIFICANCE STATEMENT: This study aimed to evaluate the antitumor effect of cambinol, a selective inhibitor of neutral sphingomyelinase 2, and its combination with apalutamide as a potential therapeutic strategy for metastatic castration-resistant prostate cancer.
    Keywords:  Apalutamide; Cambinol; Castration-resistant prostate cancer; Cell proliferation; Migration; n-SMase2 inhibition
    DOI:  https://doi.org/10.1016/j.jpet.2025.103739
  41. Front Oncol. 2025 ;15 1656216
    Efficacy and safety of apalutamide, abiraterone acetate, and bicalutamide in the treatment of metastatic hormone-sensitive prostate cancer.
    Jiabin Zhang, Qiang Wang, Junjie Zhou, Huiyu Gao, Peng Hao, Tao Wu.
       Objectives: To compare the efficacy and safety of three drugs-Apalutamide, Abiraterone, and Bicalutamide-combined with Androgen Deprivation Therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
    Methods: We retrospectively collected survival data of patients treated at our hospital from January 2019 to March 2024. Patients who received three different treatment regimens-Apalutamide (240 mg/day) combined with ADT, Abiraterone (1000 mg/day) plus Prednisone (5 mg/day) combined with ADT, and Bicalutamide (50 mg/day) combined with ADT.
    Results: This study analyzed 146 mHSPC patients. The results are displayed that Apalutamide and Abiraterone significantly prolonged PFS and PSA-PFS compared to Bicalutamide. Univariate and multivariate COX regression analyses suggested that factors such as age <75 years, absence of lymph node metastasis, use of Apalutamide or Abiraterone, and a low ECOG score were associated with longer PFS. Moreover, Apalutamide and Abiraterone showed superior efficacy in improving PSA response compared to Bicalutamide. Importantly, no life-threatening adverse events were reported in any of the three treatment groups.
    Conclusion: Compared to Bicalutamide, the novel endocrine therapies Apalutamide and Abiraterone both significantly prolong PFS, PSA-PFS, and improve PSA response rates.
    Keywords:  abiraterone acetate; androgen deprivation therapy; apalutamide; bicalutamide; endocrine therapy; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1656216
  42. Front Oncol. 2025 ;15 1640159
    Multimodal integration of [18F]PSMA-1007 PET/CT semiquantitative parameters and clinicopathological data for predicting prostate cancer metastasis.
    JiaYing Yang, ZhiLong Ma, HaiTong Hao, Jian Chen, ZhiYong Lv, Qian Zhao, YanMei Li.
       Background: Prostate cancer is one of the most prevalent malignant tumors of the male genitourinary system. The occurrence of metastasis significantly influences treatment strategies and prognosis. However, current risk assessments for metastatic disease primarily rely on single imaging or pathological indicators, which are often limited by suboptimal accuracy and considerable individual variability.
    Objective: This study aimed to develop a high-performance predictive model for prostate cancer metastasis by integrating semiquantitative parameters from [18F]PSMA-1007 PET/CTwith key clinicopathological features.
    Methods: We retrospectively analyzed data from prostate cancer patients, includingPSMA PET/CT-derived features (SUVmax, SUVmean, PSMA-TVp, TL-PSMAp) and clinical-pathological variables (age, tPSA, Gleason score). Five machine learningalgorithms-Logistic Regression, Support Vector Machine, Random Forest, Naive Bayes, and XGBoost-were evaluated for metastasis prediction performance. Model performance was assessed using accuracy, sensitivity, precision, and area under the ROC curve (AUC). Shapley additive explanations (SHAP) were applied to interpret the most effective model.
    Results: Among the five algorithms, the XGBoost model achieved an accuracy of 90.32%, sensitivity of 90.0%, specificity of 94.74%, and an AUC of 0.8977. SHAP analysis identified PSMA-TVp, TL-PSMAp as the most important predictors, followed by SUVmax, tPSA, and Gleason score. These findings highlight the key role of PSMA-derived tumor burden in metastasis prediction. Force plots further revealed the individual-level contributions of features, supporting the model's clinical interpretability.
    Conclusion: The XGBoost-based multimodal model integrating PET/CT semiquantitative parameters with clinicopathological data demonstrated excellent accuracy and interpretability in predicting prostate cancer metastasis. This approach has strong potential for clinical application and may provide a valuable tool for personalized treatment decision-making.
    Keywords:  SHAP; [18F]PSMA-1007; machine learning; multimodal prediction; positron emission tomography/computed tomography; predictingprostate cancer metastasis
    DOI:  https://doi.org/10.3389/fonc.2025.1640159
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