bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–11–30
35 papers selected by
Grigor Varuzhanyan, UCLA
  1. Effect of TGF-β mediated phenotypic changes on prostate cancer cell anoikis response.
  2. Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression.
  3. Oxidative stress reactivates androgen receptor signaling via USP36 to drive castration resistance in prostate cancer.
  4. Ferroptotic resistance involved in PTEN-loss prostate cancer progression.
  5. Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer.
  6. Icariin-curcumol inhibits histone H3K18 lactylation and FOXM1 expression to enhance the sensitivity of prostate cancer cells to docetaxel.
  7. NEUROG3 Is Sufficient to Drive Neuroendocrine Differentiation in Prostate Cancer Cells.
  8. An oncogenotype-immunophenotype paradigm governing the myeloid landscape in genetically engineered mouse models of prostate cancer.
  9. The N6-methyladenosine Modified EphA10 Promotes Prostate Cancer Progression by Activating the ERK/AKT Pathway.
  10. NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer.
  11. Targeting Prostate Cancer Cells Using Anti-Sortilin and Anti-Syndecan-1 Antibody Drug Conjugates.
  12. Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis.
  13. Radiation Reprograms Fibroblasts to Drive Prostate Cancer Therapy Resistance.
  14. Correlation between metabolic unhealth and prostate cancer -an inverse probability weighting study.
  15. Multiprobe PET Imaging: Insignia of Tumor Heterogeneity in a Case of Neuroendocrine Prostate Cancer.
  16. Targeting prostate cancer through reactive oxygen species: Advances in photothermal and sonodynamic therapies.
  17. Correction to "The MAO-B Inhibitor Selegiline Reduces the Viability of Different Prostate Cancer Cell Lines and Enhances the Effects of Anti-Androgen and Cytostatic Agents".
  18. Elevated tumor-associated androgen receptor activity correlates with poor immune infiltration and immunotherapy response across cancer types.
  19. KAT3B acts as an oncogene in PCa by mediating the succinylation of c-Myc and promoting its stability.
  20. EXPRESS: HCAR2 inhibits prostate cancer invasion and metastasis by regulating cAMP signaling pathway.
  21. Integrated Analysis of Single-Cell RNA Sequencing and Machine Learning Reveals a T Cell-Specific PANoptosis Signature Predicting Prognosis and Immunotherapy in Prostate Cancer.
  22. Unraveling the carcinogenic mechanisms of benzo[a]pyrene in prostate cancer: a multi-omics approach.
  23. NSD2 targeting reverses plasticity and drug resistance in prostate cancer.
  24. RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity.
  25. Prostate cancer: Routine NHS screening is rejected by UK expert committee.
  26. Epidemiology and treatments of neuroendocrine prostate cancer in a large commercially insured population in the US.
  27. mpMRI-based interpretable machine learning model for predicting castration-resistant prostate cancer risk.
  28. FGF12 Enhances Prostate Cancer Cell Survival via the YB1-lncRNA Axis.
  29. Comparison of the therapeutic potential of exosomes derived from different cells for the treatment of prostate cancer.
  30. Progress in targeted therapy for prostate cancer via cell surface proteins (Review).
  31. Correction: Unveiling the NEFH+ malignant cell subtype: insights from single-cell RNA sequencing in prostate cancer progression and tumor microenvironment interactions.
  32. Semi-synthetic sapogenin derivatives inhibit inflammation-induced tumorigenic signaling alterations in prostate carcinogenesis.
  33. Combination Treatment of Carboxyl Esterase 2-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhances the Inhibition of Tumor Growth by Irinotecan in PC3, a Castration-Resistant Prostate Cancer Model.
  34. A Pharmacoinformatics and Molecular Dynamics Approach to the Phytochemical Screening of Ficus hispida Fruits for Prostate Cancer Therapy.
  35. Tumor microenvironment-mediated immune evasion and resistance in prostate cancer: mechanisms, cross-talk, and therapeutic opportunities.
  1. Oncogene. 2025 Nov 22.
    Effect of TGF-β mediated phenotypic changes on prostate cancer cell anoikis response.
    Prerna R Nepali, Edgar Gonzalez-Kozlova, Maitri Anegondi, Navneet Dogra, Maddison Archer, Goutam Chakraborty, Ashutosh K Tewari, Benjamin D Hopkins, Natasha Kyprianou.
      Epithelial mesenchymal transition (EMT) circumvents anoikis (cell death upon detachment from extracellular matrix) to promote prostate metastasis and therapy resistance. In this study, we investigated how TGF-β regulated EMT-MET (mesenchymal epithelial transition) phenotypic interconversions to enhance anoikis response in pre-clinical models of prostate cancer (PCa). We used human PCa cell line models: VCaP (androgen-sensitive, TGF-β responsive); 22RV1 (castration resistant prostate cancer); LNCaP; LNCaPTβRII (LNCaP cells overexpressing TGF-β receptor II, androgen-sensitive, TGF-β responsive); C4-2B parental and C4-2B TaxR (TGF-β unresponsive, taxane resistant). We assessed their response to TGF-β (EMT inducer) and two antitumor agents (DZ-50 and cabazitaxel (CBZ)) to understand the effect of EMT priming on anoikis vulnerability. Our findings demonstrate: (1) TGF-β induces EMT in LNCaPTβRII and apoptosis in VCaP. (2) LNCaPTβRII cells are primed by EMT to anoikis (downregulation of pSRC and cofilin). (3) Metabolic changes occur at EMT-anoikis intersection in LNCaPTβRII. (4) DZ-50 overcomes CBZ resistance in C4-2B TaxR and improves response in cells and castration-resistant organoids. These studies indicate that prostate cancer cells "programmed" to undergo phenotypic EMT become vulnerable to cell death via anoikis. Exploitation of this intersection is of potential significance in overcoming resistance to taxane chemotherapy in lethal prostate cancer. The intersection between EMT and anoikis in prostate cancer cells. TGF-β responsive prostate cancer cells respond differentially to TGF-β by undergoing epithelial mesenchymal transition EMT (LNCaPTβRII and VCaP) or apoptosis (VCaP). TGF-β induced EMT further sensitizes LNCaPTβRII to DZ-50 induced anoikis. DZ-50-associated anoikis cell death in prostate cancer cells is associated with (i) phenotypic reprogramming (EMT to mesenchymal epithelial transition (MET)) (ii) inactivation of SRC (decreased pSRC) (iii) decreased cofilin expression in LNCaPTβRII and VCaP cells.
    DOI:  https://doi.org/10.1038/s41388-025-03600-z
  2. Chin Med J (Engl). 2025 Nov 21.
    Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression.
    Hekang Ding, Qingwei Meng, Jun Zhou, Li Chen, Jiaoti Huang, Bing Zhao, Lingfan Xu.
       ABSTRACT: Prostate cancer (PCa) is one of the most common malignancies worldwide, and metabolic reprogramming plays a crucial role, particularly in tumor progression and therapeutic resistance. As PCa progresses into advanced stages, such as castration-resistant prostate cancer, significant alterations in tumor metabolic pathways, including glycolysis, amino acid utilization, and lipid acid metabolism, occur. These reprogrammed metabolic pathways support the survival and proliferation of tumor cells in altered tumor microenvironments. Glutamine metabolism is significant in advanced PCa because this pathway not only contributes to the tricarboxylic acid cycle by providing energy and carbon skeletons but also supports the synthesis of macromolecules such as nucleotides and lipids and acts as a key driver of therapeutic resistance. In addition, pioneer transcription factors, such as the androgen receptor, either regulate the activity of metabolic pathways or are influenced by specific signaling metabolites. Targeting metabolic vulnerability is an ideal therapeutic strategy for advanced PCa. The aim of this review was to describe distinct metabolic features in different stages of PCa and highlight how to improve therapeutic effects by targeting tumor metabolism.
    Keywords:  Castration-resistant prostate cancer; Glutamine metabolism; Metabolic reprogramming; Prostate cancer; Targeted therapy
    DOI:  https://doi.org/10.1097/CM9.0000000000003844
  3. Sci Rep. 2025 Nov 26. 15(1): 42185
    Oxidative stress reactivates androgen receptor signaling via USP36 to drive castration resistance in prostate cancer.
    Changhui Fan, Zhiheng Huang, Junfeng Gao, Yulong Gu, Ning Wang, Bo Zhou.
      Castration-resistant prostate cancer (CRPC) often emerges within a few years following androgen deprivation therapy, and therapeutic options remain limited. Androgen deprivation induces oxidative stress in prostate cancer (PCa) cells, leading to aberrant activation of androgen receptor (AR) signaling. This study aims to clarify the molecular mechanism underlying oxidative stress-induced AR activation in CRPC. Transcriptional activity of the prostate-specific antigen (PSA) promoter was evaluated using a dual-luciferase reporter assay under various treatments. To identify AR-interacting proteins under oxidative stress, TurboID-mediated proximity biotin labeling coupled with mass spectrometry was employed following H2O2 exposure. Protein-protein interactions between AR and ubiquitin-specific peptidase 36 (USP36) were validated by co-immunoprecipitation (Co-IP). Subcellular AR expression was assessed via Immunofluorescence in PCa cells. Low doses H2O2 (10 and 20 μM) enhanced viability and induced oxidative stress in PCa cells, and these concentrations were therefore selected for subsequent experiments. H2O2 treatment activated the AR-PSA signaling axis. The deubiquitinating enzyme USP36 was identified among the proteins that interact with AR upon H2O2 stimulation. Co-IP confirmed the specific binding between AR and USP36. Functional studies revealed that USP36 deubiquitinates and stabilizes AR. Notably, knockdown of USP36 abolished H2O2-induced activation of the AR-PSA pathway. H2O2 promotes the interaction between USP36 and AR, resulting in AR stabilization, transcriptional activation of PSA, and conferring androgen resistance. These findings provide mechanistic insights into how oxidative stress reactivates AR signaling in PCa and highlight potential therapeutic strategies for different stages of PCa.
    Keywords:  Androgen receptor; Oxidative stress; Prostate cancer; Prostate-specific antigen; Ubiquitin specific peptidase 36
    DOI:  https://doi.org/10.1038/s41598-025-25964-8
  4. Discov Oncol. 2025 Nov 25. 16(1): 2166
    Ferroptotic resistance involved in PTEN-loss prostate cancer progression.
    Yaoyao Jing, Donghui Xing, Zhigang Zhao, Xiaofang Wang.
      Ferroptosis, a newly recognized form of regulated cell death characterized by iron accumulation and lipid peroxidation, plays a pivotal role in cancer development. Herein, we investigated the mechanisms of ferroptotic resistance mediated by Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in prostate cancer cells. The ferroptosis inducer Erastin was used to evaluate the effects on cell viability, colony formation, and Reactive Oxygen Species (ROS) level in three prostate cancer cell lines: PTEN wild-type (DU145 cells) and two of the PTEN null cells (PC3 and LNCaP cells). DU145 cells were prone to ferroptosis, whereas PC3 and LNCaP cells exhibited reduced sensitivity to Erastin-induced ferroptosis. Mechanistically, PTEN loss increased Glutathione peroxidase 4 (GPX4) expression and subsequently decreased intracellular ROS level, which was associated with elevated GPX4 mRNA levels. Knockdown of GPX4 by RNAi reversed the resistance of PTEN-deficient PC3 and LNCaP cells to Erastin. Collectively, our findings suggest that ferroptosis can serve as a potential therapeutic strategy for prostate cancer, and PTEN status may influence cellular sensitivity to ferroptosis.
    Keywords:  Ferroptosis; GPX4; PTEN; Prostate cancer
    DOI:  https://doi.org/10.1007/s12672-025-03990-2
  5. Oncogene. 2025 Nov 24.
    Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer.
    Yongtao Li, Zhicheng Zhou, Yiqun Zhang, Deyong Jia, Ding Wang, Mary C Reiger, Chad J Creighton, Peter S Nelson, Eva Corey, Colm Morrissey, Li Xin.
      Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.
    DOI:  https://doi.org/10.1038/s41388-025-03631-6
  6. Cancer Cell Int. 2025 Nov 25. 25(1): 423
    Icariin-curcumol inhibits histone H3K18 lactylation and FOXM1 expression to enhance the sensitivity of prostate cancer cells to docetaxel.
    Wen Sheng, Yingqiu Li, Tao Tan, Xincheng Yu, Xuxi Huang, Lingyi Li, Canying Zhang, Yalin Chen, Lumei Liu, Min Feng, Haitao Dang, Qinghu He, Wenjing Xu.
       BACKGROUND: Histone lactylation has emerged as an epigenetic driver of tumor chemoresistance. Our prior work identified the phytochemical combination icariin-curcumol (Ica-Cur) as a potential therapeutic agent against docetaxel (DTX)-resistant prostate cancer (PCa). This study aimed to investigate the mechanistic link between histone lactylation and DTX resistance in PCa, and evaluates Ica-Cur's regulatory role in this process.
    METHODS: DTX-resistant LNCaP/R cells were generated from parental LNCaP PCa cells. Xenograft models were established in BALB/c nude mice using both cell lines. Interventions included pharmacological modulation of glycolysis (sodium lactate [Nala], a glycolysis activator and 2-deoxy-D-glucose [2-DG], a glycolysis inhibitor) and genetic silencing of forkhead box M1 (FOXM1) via lentiviral constructs (sh-FOXM1). The enrichment of histone H3K18 lactylation (H3K18la) at the FOXM1 promoter was validated. Tumor growth, lactate levels, lactate dehydrogenase (LDH) activity, proliferation, and apoptosis were systematically analyzed.
    RESULTS: Resistant LNCaP/R models exhibited significant upregulation of H3K18la and FOXM1 compared to controls. Nala increased lactate production, enhanced H3K18la deposition, and stimulated proliferation while suppressing apoptosis. Conversely, 2-DG reduced H3K18la deposition and inhibited proliferation. FOXM1 expression was directly regulated by H3K18la, with sh-FOXM1 reducing LDH activity, inhibiting proliferation, and inducing apoptosis. Ica-Cur restored DTX sensitivity by suppressing H3K18la and FOXM1 expression.
    CONCLUSION: These findings identify H3K18la-mediated FOXM1 activation as a novel mechanism underlying DTX resistance in PCa. Ica-Cur may represent a promising therapeutic agent by targeting lactylation-dependent epigenetic regulation and FOXM1-driven transcriptional activity, supporting its clinical potential for overcoming chemoresistance.
    Keywords:  Chemotherapy resistance; FOXM1; Histone lactylation; Prostate cancer
    DOI:  https://doi.org/10.1186/s12935-025-03927-3
  7. bioRxiv. 2025 Nov 12. pii: 2025.11.10.687642. [Epub ahead of print]
    NEUROG3 Is Sufficient to Drive Neuroendocrine Differentiation in Prostate Cancer Cells.
    Abdelkader Daoud, Lu Han, Rachael K Christensen, Jorge O Múnera.
      Treatment-emergent neuroendocrine prostate cancer (t-NEPC) arises following androgen deprivation therapy, leading to androgen-independent growth. Although multiple factors have been shown to be necessary for neuroendocrine differentiation (NED), their sufficiency has not been demonstrated. The prostate and colorectum share a common hindgut origin, and prostate neuroendocrine cell markers overlap with colorectal enteroendocrine cell (EEC) markers. Analysis of patient datasets revealed NEUROG3 amplification in both castration-resistant and neuroendocrine prostate cancers, correlating with poor survival. Because Neurogenin-3 (NEUROG3) is necessary and sufficient for EEC differentiation in the colorectum, we hypothesized that it could similarly drive NED in prostate cancer cells. A transient pulse of NEUROG3 repressed luminal identity and activated neuroendocrine programs, producing neuroendocrine cells within seven days. In summary, our findings identify NEUROG3 as a potential mediator of prostate cancer progression and establish a rapid in vitro model in which its transient activation is sufficient to initiate neuroendocrine differentiation.
    DOI:  https://doi.org/10.1101/2025.11.10.687642
  8. bioRxiv. 2025 Oct 22. pii: 2025.10.21.683668. [Epub ahead of print]
    An oncogenotype-immunophenotype paradigm governing the myeloid landscape in genetically engineered mouse models of prostate cancer.
    Yuting Zhang, Yaoyin Li, Dailin Gan, Yan Liu, Xin Lu.
      Distinct oncogenotypes sculpt divergent myeloid landscapes in prostate cancer. Using prostate-specific Ptenpc-/-, Ptenpc-/- Trp53pc-/-, Ptenpc-/- Smad4pc-/-, and Ptenpc-/- Trp53pc-/- Smad4pc-/- models, we identify a Smad4-loss-driven neutrophil-enriched subtype (NES) characterized by CXCL5, CXCL2, and CCL20 upregulation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration, and immune checkpoint resistance. In contrast, Smad4-intact tumors form macrophage-enriched subtypes (MES) responsive to immunotherapy. Mechanistically, Smad4 ablation activates YAP signaling and elevates histone epigenetic regulatory enzymes that enhance histone modification, chromatin accessibility, and transcription of neutrophil-recruiting cytokines. Genetic or pharmacologic inhibition of these enzymes suppresses chemokine expression, reduces neutrophil accumulation, restores CD8 T-cell activity, and limits tumor growth in immunocompetent hosts. Analyses of human prostate cancers support the findings from the murine NES prostate tumors. These findings establish a Smad4-YAP-epigenetic axis linking oncogenotype to immunophenotype and uncover a therapeutic vulnerability within the myeloid-dominant prostate tumor microenvironment.
    DOI:  https://doi.org/10.1101/2025.10.21.683668
  9. Biochem Genet. 2025 Nov 26.
    The N6-methyladenosine Modified EphA10 Promotes Prostate Cancer Progression by Activating the ERK/AKT Pathway.
    Liang Hu, Jianyong Tong, Daxue Tian, Quanqi Liu.
      Prostate cancer (PCa) is highly aggressive and poses significant threats to health. Investigating the molecular regulatory mechanisms that potentially inhibit tumor progression is essential to identifying valuable target genes for therapeutic intervention. Bioinformatics techniques were employed to explore potential key target genes. siRNA interference was used to construct gene knockdown cell models. Dot blot and MeRIP-qPCR techniques are utilized to investigate the overall N6-methyladenosine (m6A) methylation levels of the target gene. qRT-PCR was used to evaluate the mRNA expression levels of the genes, while Western blotting analysis was performed to detect the protein expression levels of the target genes. The results from bioinformatics, Western blotting and qRT-PCR demonstrate that EphA10 is significantly overexpressed in PCa, highlighting its potential as a target gene for PCa. Mechanistically, EphA10 mRNA undergoes m6A modification mediated by RBM15B, which enhances its stability and expression. YTHDF1 has been identified as an m6A reader for EphA10, promoting its stability and expression in an m6A-dependent manner. Furthermore, the study reveals that m6A-modified EphA10 accelerates PCa cell proliferation, invasion, and migration by activating the ERK/AKT signaling pathway. Our findings suggest that PCa stabilizes the m6A methylation of EphA10, thereby sustaining the activation of the ERK/AKT signaling pathway and accelerating cancer progression. Targeting EphA10, or the m6A methylation "writer" and "reader" proteins involved in its regulation, to inhibit this methylation process could represent a promising therapeutic strategy for PCa.
    Keywords:  ERK/AKT; EphA10; N6-methyladenosine; Prostate cancer
    DOI:  https://doi.org/10.1007/s10528-025-11299-6
  10. bioRxiv. 2025 Nov 13. pii: 2025.11.12.687734. [Epub ahead of print]
    NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer.
    Umar Mehraj, Uran Maimekov, Shaista Manzoor, Emily Cordova, Manasiben Patel, Ikeer Y Mancera-Ortiz, Stefanie Howell, Zachary W Davis-Gilbert, Mu-En Wang, Ming Chen, Jung Wook Park, Yuzhuo Wang, Andrew J Armstrong, Jiaoti Huang, David H Drewry, Antonina Mitrofanova, Everardo Macias.
      Prostate cancer (PC) remains the second leading cause of cancer-related mortality in men. The emergence of treatment-emergent neuroendocrine prostate cancer (NEPC) arising from androgen receptor (AR) pathway inhibition poses a significant clinical challenge. Here, we report that NUAK family kinase 2 (NUAK2) is an actionable therapeutic target in NEPC. NUAK2 expression is markedly elevated in NEPC patient specimens and preclinical models, and its genetic or pharmacologic inhibition suppresses NEPC tumor growth. The FDA-approved CDK4/6 inhibitor trilaciclib exerts potent inhibition of NUAK2, leading to marked tumor suppression alone and enhanced efficacy in combination with carboplatin. Integrated phospho-target and interactome analyses demonstrate that NUAK2 engages core spliceosome components to regulate pre-mRNA splicing. As proof of principle, we validated that NUAK2 inhibition perturbs pre-mRNA splicing of EZH2 and TTK leading to reduced translation. Collectively, these findings establish NUAK2 as a clinically actionable regulator of RNA splicing and tumor progression in NEPC, revealing a novel mechanism by which trilaciclib exerts antitumor activity in NEPC.
    DOI:  https://doi.org/10.1101/2025.11.12.687734
  11. Int J Mol Sci. 2025 Nov 18. pii: 11145. [Epub ahead of print]26(22):
    Targeting Prostate Cancer Cells Using Anti-Sortilin and Anti-Syndecan-1 Antibody Drug Conjugates.
    Ka Lok Li, Shane M Hickey, Hugo Albrecht, Jessica M Logan, Joanna Lazniewska, Courtney R Moore, Robert D Brooks, Ian R D Johnson, John J O'Leary, Douglas A Brooks.
      Prostate cancer tissue usually involves either well formed glands, poorly formed glands or a combination of the two morphologies, which can be correlated with metabolic differences and tumor heterogeneity. This is particularly important for metastatic castration-resistant prostate cancer, where the heterogeneity and metabolic changes drive cancer progression and treatment refractory properties. Sortilin and syndecan-1 expression accurately define the two different morphologies in prostate cancer tissue, are critical to the process of metabolic regulation, and exhibit mechanistic/functional interactions during prostate cancer progression. As trans-membrane proteins that recycle from endocytic compartments to the cell surface, sortilin and syndecan-1 are attractive targets for therapeutic intervention that address the two major forms of prostate cancer. In this study, we describe an antibody-drug conjugate (ADC) strategy that utilizes monoclonal antibodies which bind to specific extracellular domains of these integral membrane proteins to elicit anticancer activity in prostate cancer cell lines. Anti-sortilin (clone 11H8) and anti-syndecan-1 (clone 6D11) monoclonal antibodies demonstrated high specificity for epitopes on the extracellular, N-terminal domains of these respective proteins and were effectively internalized into prostate cancer cell endocytic compartments. Monomethyl aurastatin E (MMAE)-conjugated ADCs exhibited low nanomolar cytotoxicity in LNCaP and PC-3 prostate cancer cells. Mechanistically, 11H8-MMAE and 6D11-MMAE triggered cytotoxicity and morphological alterations in androgen-sensitive and androgen-insensitive cells. However, the uptake of fluorescent labelled 11H8 and 6D11 antibodies appeared to be high, whereas the killing capacity of the MMAE-conjugated antibodies was less impressive, suggesting the need for further ADC development. These promising proof-of-concept ADCs are designed to exploit molecular and metabolic vulnerabilities in prostate cancer and may have utility for overcoming treatment resistance by simultaneously targeting different forms of the cancer.
    Keywords:  advanced cancer; antibody drug conjugates; monoclonal antibodies; prostate cancer; therapeutics
    DOI:  https://doi.org/10.3390/ijms262211145
  12. JCI Insight. 2025 Nov 24. pii: e195743. [Epub ahead of print]10(22):
    Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis.
    Xiaodong Lu, Liu Peng, Qi Chu, Samantha Ye, Mingyang Liu, Maha Hussain, Mehmet A Bilen, Lara R Harik, Jonathan Melamed, Jonathan C Zhao, Jindan Yu.
      HOXB13 is a prostate-specific transcription factor best known for its role as an androgen receptor (AR) cofactor. Recent evidence suggests that HOXB13 plays critical AR-independent functions in repressing lipogenic programs and promoting prostate cancer (PCa) metastasis. However, the mechanisms linking HOXB13 loss to tumor metastasis remain unclear. Here, we show that p300 and CBP co-occupy lipogenic enhancers suppressed by HOXB13 and HDAC3 and are essential for enhancer activation and target gene expression following HOXB13 depletion. Loss of HOXB13 induces lipid-sensitive matrix metalloproteinases (MMPs), promoting increased cell motility. Importantly, pharmacological inhibition of p300 and CBP blocks HOXB13-loss-driven lipogenesis, reduces MMP expression, and decreases cell migration in vitro and tumor metastasis in vivo. Analysis of clinical samples revealed that HOXB13 expression is reduced in metastatic hormone-sensitive PCa compared with matched primary tumors, further supporting its role in tumor metastasis. These findings demonstrate that HOXB13 downregulation promotes PCa metastasis through p300- and CBP-dependent lipogenic and motility pathways, which may be targeted by p300 inhibition.
    Keywords:  Drug therapy; Epigenetics; Genetics; Oncology; Prostate cancer
    DOI:  https://doi.org/10.1172/jci.insight.195743
  13. Endocr Relat Cancer. 2025 Nov 25. pii: ERC-25-0221. [Epub ahead of print]
    Radiation Reprograms Fibroblasts to Drive Prostate Cancer Therapy Resistance.
    Anisha Madhav, Manish Thiruvalluvan, Frank Duong, Krizia Rohena-Rivera, Rajeev Mishra, Sandrine Billet, Manisha Tripathi, Bryan Angara, Aleksandr Stotland, Allen Andres, Zhenqiu Liu, Roberta A Gottlieb, Zachary S Zumsteg, Neil A Bhowmick.
      Radiotherapy is a mainstay treatment for localized prostate cancer (PCa). Yet, radiation resistance remains a major clinical obstacle. Here, radiation induced a BMP/CD105-dependent metabolic shift in the tumor microenvironment that facilitates PCa cell survival. Using prostate tumor models and fibroblast cultures, we show that radiation enhances epithelial BMP ligand production which promotes fibroblastic CD105 signaling. Metabolomic analysis upon radiation revealed that fibroblastic CD105 signaling elevated key enzymes involved in mitochondrial biogenesis (PGC1α) and ketogenesis (HMGCS2). The increased production of β-hydroxybutyrate in the tumor microenvironment sustained PCa cell energy metabolism and enhanced DNA repair upon radiation stress. Blocking BMP signaling through carotuximab (ENV105), a CD105-targeting antibody, disrupted epithelial-fibroblast crosstalk, resulting in decreased β-hydroxybutyrate within the tumor microenvironment. This attenuation of fibroblast-mediated metabolic support increased DNA damage and apoptosis, sensitizing PCa cells to radiation. In subcutaneous mouse models, grafting PCa cells with CD105-KO or HMGCS2-KO fibroblasts yielded smaller tumors following radiation compared with wild-type fibroblast controls. Across subcutaneous and orthotopic models, combined treatment with carotuximab and irradiation reproducibly achieved superior tumor volume reduction relative to single-agent therapy. This study identified the BMP/CD105 axis as a key pathway in radiation resistance, highlighting the potential of targeting fibroblastic CD105 with carotuximab to enhance radiation sensitivity.
    Keywords:  Fibroblast; ketones; prostate cancer; radiation resistance
    DOI:  https://doi.org/10.1530/ERC-25-0221
  14. BMC Urol. 2025 Nov 24. 25(1): 295
    Correlation between metabolic unhealth and prostate cancer -an inverse probability weighting study.
    Mingyue Chen, Yijie Zhou, Jinru Wang, Hao Qiu, Hengqing An, Ning Tao.
       BACKGROUND: Current research indicates that prostate cancer (PCa) is one of the most common cancers in men, and its occurrence may be linked to metabolic unhealth. Therefore, we conducted a study on the correlation between metabolic unhealth and PCa.
    OBJECTIVE: To study the correlation between metabolic unhealth and the incidence of PCa.
    METHODS: A total of 607 patients underwent prostate biopsy in the urology department of a certain tertiary hospital in Urumqi, Xinjiang from May 2018 to September 2022. Age was used as a matching variable inverse probability weighted to reduce the influence of confounding factors. Logistic regression models were used to analyze the association between metabolic unhealthiness and the risk of prostate cancer.
    RESULTS: (1) Logistic regression analysis showed that the risk of prostate cancer in metabolically unhealthy people was 1.684 times higher than that in metabolically healthy people (OR=1.684,95%CI:1.224-2.317,P=0.001); (2) In sensitivity analysis, multifactor Poisson regression showed that metabolically unhealthy people had higher risk of the disease (RR=1.145, 95%CI:1.015-1.292, P =0.028). Subsequently, excluding those with diabetes, sensitivity analysis using inverse probability-weighted logistic regression with age as a matching variable showed that those with unhealthy metabolism had a higher risk of prostate cancer (OR=1.464,95% CI:1.046-2.050, P =0.026).
    CONCLUSION: Metabolic unhealth, obesity, are risk factors for PCa, which have certain diagnostic and therapeutic value for the risk of PCa. Reducing body weight and managing blood pressure, blood sugar, blood lipids, and high-density lipoprotein through reasonable diet can effectively prevent and control PCa.
    Keywords:  Metabolic Unhealth; Obesity; Prostate Cancer
    DOI:  https://doi.org/10.1186/s12894-025-01969-3
  15. Clin Nucl Med. 2025 Oct 15.
    Multiprobe PET Imaging: Insignia of Tumor Heterogeneity in a Case of Neuroendocrine Prostate Cancer.
    Akshay Bedmutha, Bruce Barron, Stephen Lau, Kyle Oi, David Brandon.
      Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, often developing from androgen receptor (AR) independence, characterized by neuroendocrine molecular markers and nonresponsiveness to standard treatments of prostate adenocarcinoma. The evolution of adenocarcinoma to NEPC is characterized by epigenetic changes, leading to the downregulation of the PSMA transmembrane protein, as well as the upregulation of FDG-uptake pathways and somatostatin receptor expression. We present a case of NEPC that depicts a significant metastatic intertumoral heterogeneity as depicted on PSMA, FDG, and DOTATATE PET/CT scans. Such multiprobe PET evaluation of NEPC may assist in sampling the most aggressive disease and guide an appropriate management strategy. It also provides a cellular-level insight into this dreadful disease with very limited treatment options.
    Keywords:  DOTATATE; FDG; PET/CT; PSMA; neuroendocrine; prostate cancer; tumor heterogeneity
    DOI:  https://doi.org/10.1097/RLU.0000000000006182
  16. Nanomedicine. 2025 Nov 23. pii: S1549-9634(25)00082-6. [Epub ahead of print]71 102881
    Targeting prostate cancer through reactive oxygen species: Advances in photothermal and sonodynamic therapies.
    Ridha M Lefta, Samer Saleem Alshkarchy, Thekra F Ali, Majid S Jabir, Wesam R Kadhum.
      Prostate cancer (PCa) remains a major clinical challenge due to limited treatment efficacy, frequent resistance, and high recurrence rates. Given the susceptibility of cancer cells to oxidative stress, reactive oxygen species (ROS)-based strategies offer promising therapeutic potential. Photothermal therapy (PTT) and sonodynamic therapy (SDT) are emerging minimally invasive modalities that exploit nanotechnology to induce localized ROS generation. This review highlights recent advances in ROS-mediated PTT and SDT for PCa, emphasizing nanomaterial design and functionalization to enhance targeting precision, drug delivery, and overcome tumor hypoxia. Combining PTT and SDT with chemotherapy, radiotherapy, or immunotherapy produces synergistic effects, potentially overcoming resistance and eliciting systemic antitumor immunity. Preclinical studies demonstrate effective tumor eradication and immune activation with minimal toxicity, suggesting promise for clinical translation. However, human clinical trials remain scarce, and further translational research is needed before these nanotechnology-based approaches can be integrated into standard PCa treatment.
    Keywords:  Cancer; Nanotechnology; Photothermal therapy; Sonodynamic therapy; Ultrasound
    DOI:  https://doi.org/10.1016/j.nano.2025.102881
  17. Pharmacol Res Perspect. 2025 Dec;13(6): e70198
    Correction to "The MAO-B Inhibitor Selegiline Reduces the Viability of Different Prostate Cancer Cell Lines and Enhances the Effects of Anti-Androgen and Cytostatic Agents".
      
    DOI:  https://doi.org/10.1002/prp2.70198
  18. Cancer Res Commun. 2025 Nov 26.
    Elevated tumor-associated androgen receptor activity correlates with poor immune infiltration and immunotherapy response across cancer types.
    Ya-Mei Hu, Faming Zhao, Julie N Graff, Canping Chen, Yi Zhang, Jayne M Stommel, Jinho Lee, Gabriel M Zangirolani, Joshua Rose, George V Thomas, Hui Wu, Adel Kardosh, Gordon B Mills, Joshi J Alumkal, Amy E Moran, Zheng Xia.
      The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. Here, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA-seq (TCGA), single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and ssGSEA. Key findings were validated using Digital Spatial Profiling and immunohistochemistry. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, highest in prostate adenocarcinoma. Genes significantly correlated with AR activity show negative associations and are enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFN-γ pathway activity across tumors and sexes-unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed AR inhibition enhanced immune cell and IFN-γ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0409
  19. World J Surg Oncol. 2025 Nov 27.
    KAT3B acts as an oncogene in PCa by mediating the succinylation of c-Myc and promoting its stability.
    Wei Nie, Shifang Cha, Quanwei Fu.
       BACKGROUND: As a form of protein modification, succinylation significantly impacts protein function and helps govern a range of signaling mechanisms. This study was designed to explore the role of KAT3B, functioning as a succinylase, in the context of prostate cancer (PCa).
    METHODS: The expression levels were assessed using quantitative real-time PCR, Western blot, and immunofluorescence staining. To investigate protein-protein interactions, immunoprecipitation assays were performed. The interaction between proteins were confirmed by Co-immunoprecipitation assay. The cell phenotype of PCa cells was analyzed by CCK-8, flow cytometry, and transwell assays.
    RESULTS: We found that KAT3B was over-expressed in PCa tumor tissues and cells. Downregulated KAT3B decreased the viability, migration, and invasion while accelerating the apoptosis of PCa cells. Mechanistically, KAT3B mediated the succinylation of c-Myc, meantime promoted the stability of c-Myc. c-Myc overexpression reversed the role of KAT3B in PCa cells. The in vivo study verified that KAT3B silencing inhibited the growth of PCa cancer tissues.
    CONCLUSION: Our research indicates that KAT3B was highly expressed in PCa. KAT3B silencing inhibited PCa cell growth and cancer tissues growth by decreasing the succinylation and expression of c-Myc. These findings potentially contribute to novel approaches in diagnosing and treating PCa.
    Keywords:  C-Myc; KAT3B; Prostate cancer; Succinylation
    DOI:  https://doi.org/10.1186/s12957-025-04068-7
  20. J Investig Med. 2025 Nov 28. 10815589251406272
    EXPRESS: HCAR2 inhibits prostate cancer invasion and metastasis by regulating cAMP signaling pathway.
    Yanmin Li, Hanmin Chen, Ruohui Huang.
       BACKGROUND: Prostate cancer (PCa) is one of the most prevalent malignancies affecting men and a significant contributor to the rising global cancer-related mortality rate. Nevertheless, intricate processes underlying invasion and metastasis remain largely unclear. Objective of our research was to explore the function and underlying mechanisms of HCAR2 in the invasion and metastasis of PCa.
    METHODS: We analyzed differentially expressed genes in PCa through transcriptome sequencing. Then, we conducted bioinformatics analyses to investigate the correlation between HCAR2 and PCa. Furthermore, we overexpressed HCAR2 both in vitro and in vivo to investigate its role in regulating the proliferation and invasion of PCa cells as well as the tumorigenic ability of PCa cells. Finally, we treated PC3 cells with the signaling pathway inhibitor H89 on the basis of HCAR2 overexpression to explore the role of the cAMP signaling pathway in PCa.
    RESULTS: HCAR2 was significantly downregulated in PCa patients. HCAR2 had diagnostic significance for the survival prognosis of PCa patients, with a high diagnostic accuracy rate over a five-year period. The core targets of HCAR2 in PCa were involved in the cAMP signaling pathway. Furthermore, overexpression of HCAR2 repressed the proliferation, migration, and invasion abilities of PC3 and DU145 cells, as well as the tumorigenic ability of PCa cells in vivo. Finally, H89 treatment reversed the effects of HCAR2 overexpression on cAMP signaling pathway-related proteins, as well as on the proliferation, migration, and invasion abilities of PC3 cells.
    CONCLUSIONS: HCAR2 inhibited the proliferation and invasion of PCa cells through cAMP signaling pathway.
    Keywords:  Medicine
    DOI:  https://doi.org/10.1177/10815589251406272
  21. Hum Mutat. 2025 ;2025 8889021
    Integrated Analysis of Single-Cell RNA Sequencing and Machine Learning Reveals a T Cell-Specific PANoptosis Signature Predicting Prognosis and Immunotherapy in Prostate Cancer.
    Hua Wang, Wenjin Li, Weiming Deng, Jianjie Wu, Ke Li, Xi Huang.
       Background: Prostate cancer (PCa) ranks among the most prevalent malignancies, with prognosis heavily influenced by diagnostic stage. The role of PANoptosis in T cell-based immunotherapy has garnered growing attention recently. This study is aimed at establishing a T cell-specific PANoptosis signature (TSPS) to predict prognosis and immunotherapy response in patients with PCa.
    Methods: Single-cell RNA sequencing (scRNA-seq) data from the GSE185344 dataset were used to identify T cell-specific genes. A comprehensive machine learning pipeline incorporating 10 distinct algorithms was employed to construct a consensus prognostic TSPS.
    Results: The scRNA-seq analysis identified T cells as the predominant cell type, and cell-cell communication analysis indicated heightened activation of specific immune-related signaling pathways in PCa. A consensus prognostic signature comprising nine key genes was developed, demonstrating superior predictive accuracy for clinical outcomes compared to conventional clinical variables. A TSPS-based nomogram was also constructed, displaying strong predictive capability for survival outcomes in patients with PCa. Patients in the high-risk group exhibited greater intratumor heterogeneity, increased immune infiltration, and higher immunosuppression scores, suggesting reduced immunotherapy benefits. Validation with four independent immunotherapy cohorts verified that patients in the low-risk group exhibited more favorable immunotherapy responses. Additionally, 18 compounds were determined as therapeutic options for high-risk patients with PCa. In vitro experiments demonstrated that UBB expression was upregulated in PCa, and UBB knockdown significantly inhibited PCa cell proliferation and invasion.
    Conclusion: We established a consensus prognostic TSPS for PCa, offering a potential foundation for future personalized approaches in risk stratification, prognostic evaluation, and treatment selection for patients with PCa.
    Keywords:  PANoptosis; immunotherapy; machine learning; prognostic signature; prostate cancer; single-cell RNA sequencing
    DOI:  https://doi.org/10.1155/humu/8889021
  22. Naunyn Schmiedebergs Arch Pharmacol. 2025 Nov 25.
    Unraveling the carcinogenic mechanisms of benzo[a]pyrene in prostate cancer: a multi-omics approach.
    Jiansheng Xiao, Handa Zheng, Guohao Wu, Ping Li, Qiyu Zhong, Qiao Lv, Jiahui Chen, Caiyong Lai, Dongming Ye.
      Although cigarette smoke is a recognized risk factor for prostate cancer (PCa), the specific contribution of benzo[a]pyrene (BaP), one of its major carcinogenic constituents, remains poorly understood. To elucidate the pathogenic mechanisms of BaP in PCa, this study integrated diverse methodologies, including network toxicology, single-cell transcriptomics, differential gene expression analysis, molecular docking, Mendelian randomization (MR), and bibliometrics. Two hundred thirty-two overlapping genes were identified between BaP targets and PCa-related genes. Hub genes TP53, EGFR, SRC, HSP90AA1, and INS were enriched in MAPK and PI3K-Akt pathways. Molecular docking confirmed strong BaP binding to these proteins. Single-cell transcriptomics revealed cell-type-specific expression patterns, while ROC (TP53 AUC = 0.67) and MR analyses (TP53 p = 2.66 × 10⁻⁶) supported their diagnostic and causal relevance. TP53 showed notable expression variability linked to Gleason scores. Bibliometric analysis highlighted TP53's evolving research significance in PCa, particularly in resistance and personalized therapy. BaP may drive PCa progression by disrupting oncogenic pathways via core targets, notably TP53, EGFR, and HSP90AA1. TP53 may act as a protective factor associated with tumor aggressiveness. These findings offer mechanistic insights into BaP-related PCa etiology and suggest potential biomarkers for diagnosis and therapy.
    Keywords:  Benzo[a]pyrene; Mendelian randomization; Multi-omics; Network toxicology; Prostate cancer
    DOI:  https://doi.org/10.1007/s00210-025-04842-0
  23. Nature. 2025 Nov 26.
    NSD2 targeting reverses plasticity and drug resistance in prostate cancer.
    Jia J Li, Alessandro Vasciaveo, Dimitris Karagiannis, Zhen Sun, Kristjan H Gretarsson, Xiao Chen, Ouathek Ouerfelli, Fabio Socciarelli, Ziv Frankenstein, Hanyang Dong, Min Zou, Wei Yuan, Guangli Yang, Gabriel M Aizenman, Tania Pannellini, Xinjing Xu, Himisha Beltran, Yu Chen, Kevin Gardner, Brian D Robinson, Johann de Bono, Or Gozani, Cory Abate-Shen, Mark A Rubin, Massimo Loda, Charles L Sawyers, Andrea Califano, Chao Lu, Michael M Shen.
      Lineage plasticity is a cancer hallmark that drives disease progression and treatment resistance1,2. Plasticity is often mediated by epigenetic mechanisms that may be reversible; however, there are few examples of such reversibility. In castration-resistant prostate cancer (CRPC), plasticity mediates resistance to androgen receptor (AR) inhibitors and progression from adenocarcinoma to aggressive subtypes, including neuroendocrine prostate cancer (CRPC-NE)3-5. Here we show that plasticity-associated treatment resistance in CRPC can be reversed through the inhibition of NSD2, a histone methyltransferase6. NSD2 upregulation in CRPC-NE correlates with poor survival outcomes, and NSD2-mediated H3K36 dimethylation regulates enhancers of genes associated with neuroendocrine differentiation. In prostate tumour organoids established from genetically engineered mice7 that recapitulate the transdifferentiation to neuroendocrine states, and in human CRPC-NE organoids, CRISPR-mediated targeting of NSD2 reverts CRPC-NE to adenocarcinoma phenotypes. Moreover, a canonical AR program is upregulated and responses to the AR inhibitor enzalutamide are restored. Pharmacological inhibition of NSD2 with a first-in-class small molecule reverses plasticity and synergizes with enzalutamide to suppress growth and promote cell death in human patient-derived organoids of multiple CRPC subtypes in culture and in xenografts. Co-targeting of NSD2 and AR may represent a new therapeutic strategy for lethal forms of CRPC that are currently recalcitrant to treatment.
    DOI:  https://doi.org/10.1038/s41586-025-09727-z
  24. bioRxiv. 2025 Oct 08. pii: 2025.10.07.681000. [Epub ahead of print]
    RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity.
    Yuyin Jiang, Siyuan Cheng, Catherine Yijia Zhang, Xiao Jin, Yaru Xu, Isaac Yi Kim, Ping Mu.
      Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of pan-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, in specific lineages. By analyzing multi-omics data, including 39 HOX genes from over 80,000 RNA-seq samples across 114 cancer types, we discovered that HOX code expression robustly represents cancer cell lineages and reveals multiple previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying altered HOX patterns compared to non-plastic subtypes. Differential analysis further identified RUNX1T1 as a novel and consistent marker of plasticity, elevated across all three cancer types and correlating with HOX code and lineage-plastic marker genes. We validated these correlations in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and provided direct functional evidence that RUNX1T1 is required for lineage-plastic programs in prostate cancer. Using AI-based modeling, we identified NCOR/HDAC as RUNX1T1 binding partners forming a co-repressor complex that regulates HOX codes and plasticity. Finally, pharmacologic HDAC inhibition selectively suppressed the growth of plastic cells, revealing a novel therapeutic vulnerability. These findings establish ectopic RUNX1T1 as a pan-cancer biomarker and critical mediator of lineage plasticity and identify the RUNX1T1-HDAC complex as a druggable target.
    DOI:  https://doi.org/10.1101/2025.10.07.681000
  25. BMJ. 2025 Nov 28. 391 r2524
    Prostate cancer: Routine NHS screening is rejected by UK expert committee.
    Jacqui Wise.
      
    DOI:  https://doi.org/10.1136/bmj.r2524
  26. Cancer Treat Res Commun. 2025 Nov 17. pii: S2468-2942(25)00174-1. [Epub ahead of print]45 101038
    Epidemiology and treatments of neuroendocrine prostate cancer in a large commercially insured population in the US.
    Zdravko Vassilev, Qayyim Said, Jihong Zong, Nasreen Khan, Christine Rentzsch, Gal Barel, Lorelei Mucci, Orsolya Lunacsek.
       BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer (PCa) subtype diagnosed de novo or arising from neuroendocrine differentiation of adenocarcinoma following androgen deprivation therapy (ADT) or antiandrogen-based therapy. The objective of the study was to describe socio-demographic and clinical characteristics at the time of NEPC diagnosis and treatment patterns prior to and after NEPC diagnosis.
    PATIENTS AND METHODS: A real-world cohort of men diagnosed with NEPC was identified using the US Optum Clinformatics® administrative claims database between 2007 and 2023. The study was descriptive in nature, without comparative analyses.
    RESULTS: Of the 607,280 patients diagnosed with PCa, 2267 (0.4%) had a diagnosis of NEPC. Median age at NEPC diagnosis was 76 years; 72% of patients were White, and half of patients had a Charlson Comorbidity Index score of 0-2 (57%). Median time from first PCa diagnosis to NEPC diagnosis was 21 months; 44% of patients with NEPC had metastases prior to NEPC diagnosis. In a subpopulation of 1767 patients with NEPC diagnosed between 2014 and 2023-representing a more recent time period with contemporary treatments-the most frequently received treatments both before and after NEPC diagnosis were radiation (39% and 31%) and ADT (34% and 25%).
    CONCLUSION: The findings of this study align with NEPC having a low real-world diagnostic prevalence among patients with PCa, especially in comparison to histology-based analyses, suggesting that treatment-induced NEPC may be underdiagnosed. This study underscores the need for further research in the NEPC population to advance diagnosis and treatment.
    Keywords:  Epidemiology; Neuroendocrine prostate cancer; Prostate cancer; Real-world data; Treatment patterns
    DOI:  https://doi.org/10.1016/j.ctarc.2025.101038
  27. Eur J Radiol. 2025 Nov 20. pii: S0720-048X(25)00607-2. [Epub ahead of print]195 112521
    mpMRI-based interpretable machine learning model for predicting castration-resistant prostate cancer risk.
    Siang Shen, Bitian Liu, Yutong Li, Yiying Zeng, Shanshan Ren, Rui Yin, Han Ma, Shen Pan.
       RATIONALE AND OBJECTIVES: Androgen deprivation therapy (ADT) efficacy exhibits significant interindividual heterogeneity in advanced prostate cancer (PCa). This study aim to develop and validate a machine learning model based on multiparametric MRI (mpMRI) to predict the risk of Castration-Resistant Prostate Cancer (CRPC) progression in advanced PCa.
    MATERIALS AND METHODS: In this retrospective study, 180 advanced PCa patients who underwent mpMRI before ADT were collected from two hospitals between January 2014 and October 2024. Radiomic features were selected by using variance threshold, Least Absolute Shrinkage and Selection Operator and recursive feature elimination. Random forest and logistic regression model selected clinical features. We developed eight machine learning classifiers, a stacking ensemble model by integrating the optimally performing classifier. Model performance was evaluated using confusion matrices, accuracy, precision, recall, F1-score, and area under curve (AUC). SHapley Additive exPlanations was employed for both global and local model interpretability. Intergroup differences were analyzed using one-way Analysis of Variance or Kruskal-Wallis tests.
    RESULTS: 180 patients (mean age 72, range 51-90 years) were stratified by the time to CRPC into groups: very high-risk (<1 year, n = 49), high-risk (1-4 years, n = 65) and low-risk (>4 years, n = 66). The mpMRI-clinical combined model performed better than mpMRI-alone model (AUC:0.84;95 %CI:0.73, 0.92).The stacking model further enhanced CRPC prediction, internal test set (AUC: 0.89; 95 %CI:0.81, 0.93) and external test set (0.82; 95 %CI:0.72, 0.89). In low-risk group, stacking model demonstrated the strongest discriminative capability AUC (0.89;95 %CI:0.77, 0.97).
    CONCLUSION: The Stacking model demonstrated favorable predictive capability for CRPC progression risk in advanced Pca, facilitating clinically actionable risk-stratified interventions.
    Keywords:  Androgen deprivation therapy; Castration-resistant prostate cancer; Machine learning; Multiparametric magnetic resonance imaging; Prostate cancer
    DOI:  https://doi.org/10.1016/j.ejrad.2025.112521
  28. Cells. 2025 Nov 20. pii: 1828. [Epub ahead of print]14(22):
    FGF12 Enhances Prostate Cancer Cell Survival via the YB1-lncRNA Axis.
    Zechao Huang, Sonia H Y Kung, Hans Adomat, Htoo Zarni Oo, Connor Forbes, Faraz Hach, Xuesen Dong.
      Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive and therapy-resistant subtype of prostate cancer characterized by lineage plasticity and poor response to standard chemotherapy and androgen deprivation therapy. Although transcriptional mechanisms driving t-NEPC have been extensively studied, the contribution of post-transcriptional regulation remains less defined. Here, we report fibroblast growth factor 12 (FGF12) as a critical post-transcriptional regulator of t-NEPC progression. Transcriptomic analyses of patient biopsies, patient-derived xenografts, and prostate cancer cell models consistently demonstrated elevated FGF12 expression in t-NEPC, which was further validated by immunohistochemistry in archival specimens. Functional assays revealed that FGF12 expression conferred survival of cancer cells to chemotherapeutic agents, including etoposide and camptothecin. Integrative RNA sequencing and affinity purification-mass spectrometry showed that FGF12 mediates these functions mainly through interaction with the RNA-binding protein YB1, leading to stabilization of oncogenic long noncoding RNAs, including NEAT1 and MALAT1, whereas RNA silencing of YB1 abrogated the ability of FGF12 to upregulate these transcripts. Collectively, these findings uncover a previously unrecognized FGF12-YB1-lncRNA signaling axis that drives t-NEPC progression. Targeting this pathway may provide new therapeutic opportunities for patients with this aggressive disease.
    Keywords:  Y-box binding protein 1 (YB1); fibroblast growth factor 12 (FGF12); long noncoding RNAs (lncRNAs); post-transcriptional regulation; treatment-induced neuroendocrine prostate cancer (t-NEPC)
    DOI:  https://doi.org/10.3390/cells14221828
  29. Crit Rev Oncol Hematol. 2025 Nov 26. pii: S1040-8428(25)00443-3. [Epub ahead of print] 105055
    Comparison of the therapeutic potential of exosomes derived from different cells for the treatment of prostate cancer.
    Farhood Khaleghi Mehr, Nikoo Emtiazi, Ehsan Zolfi, Yasaman Moradi.
      Prostate cancer (PCa) is a primary cause of male cancer death, underlining the crucial need for new therapies. Natural nanovesicles known as exosomes (EXOs) have shown great promise as therapeutic vectors due to their excellent biocompatibility, minimal immunogenicity, and inherent capacity to carry bioactive cargo. Different cell types may produce these vesicles, and each one imparts unique biological characteristics and therapeutic processes. This review compares the therapeutic potential of EXOs obtained from three primary sources for the treatment of PCa. The usefulness of mesenchymal stem cell-derived EXOs (MSC-EXOs), which leverage their inherent tumor tropism to serve as naturally occurring delivery vehicles for therapeutic agents, is critically examined. We investigate the potential of immune cell-derived EXOs (IC-EXOs) as cytotoxic agents or cell-free vaccines that effectively activate anti-tumor immunity. We also discuss the paradoxical role of tumor-derived EXOs (TEXs), which can serve as vaccine antigens or as tools for liquid biopsy, despite their role in cancer development. We highlight the unique benefits, drawbacks, and best therapeutic settings of these platforms by combining evidence from multiple platforms. Lastly, we address crucial clinical translation issues, such as manufacturing and standardization, and offer a framework for selecting the best EXO source in the evolving field of PCa treatment based on specific therapeutic goals.
    Keywords:  Exosomes; Immune cells; Prostate cancer; Treatment; Tumor-derived exosomes; mesenchymal stem cells
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105055
  30. Biomed Rep. 2026 Jan;24(1): 7
    Progress in targeted therapy for prostate cancer via cell surface proteins (Review).
    Hua Luo.
      Prostate cancer (PCa), particularly metastatic castration-resistant PCa, remains a significant therapeutic challenge. Cell-surface proteins have emerged as promising therapeutic targets. The present review examines the biological characteristics of PCa cell surface proteins focusing on major targets, such as prostate-specific membrane antigen, six-transmembrane epithelial antigen 1, trophoblast cell-surface antigen 2, and prostate stem cell antigen. These targets provide the foundation for the development of emerging therapeutic strategies, including radioligand therapy, antibody-drug conjugates, and bispecific T cells and chimeric antigen receptor T cell therapy. Combining the latest clinical trial data, the present review discusses the efficacy of targeted therapy, the mechanisms of drug therapy resistance, and combination treatment strategies, analyzing their potential application in the management of PCa and exploring prospects for the development of precision therapy in the future. Additionally, this review aims to systematically summarize the relevant progress in this field. In conclusion, the findings provide a theoretical basis and clinical guidance for molecular-targeted therapy in PCa, thereby promoting further research and applications.
    Keywords:  cell surface proteins; prostate cancer; prostate-specific membrane antigen; targeted therapy
    DOI:  https://doi.org/10.3892/br.2025.2080
  31. Front Immunol. 2025 ;16 1718125
    Correction: Unveiling the NEFH+ malignant cell subtype: insights from single-cell RNA sequencing in prostate cancer progression and tumor microenvironment interactions.
    Jie Wang, Fu Zhao, Qiang Zhang, Zhou Sun, Zhikai Xiahou, Changzhong Wang, Yan Liu, Zongze Yu.
      [This corrects the article DOI: 10.3389/fimmu.2024.1517679.].
    Keywords:  drug discovery; multi-omics; precision medicine; prostate cancer; single-cell RNA sequencing; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fimmu.2025.1718125
  32. Steroids. 2025 Nov 23. pii: S0039-128X(25)00164-3. [Epub ahead of print]225 109723
    Semi-synthetic sapogenin derivatives inhibit inflammation-induced tumorigenic signaling alterations in prostate carcinogenesis.
    Bilge Debelec-Butuner, Mert Burak Ozturk, Ozgur Tag, Ismail Hakki Akgun, Erdal Bedir.
      Prostatic inflammation plays a pivotal role in prostate cancer development and progression via altering key cellular mechanisms, including proliferation, metastasis, and angiogenesis. Therefore, the use of anti-inflammatory drugs could provide a valid contribution to PCa prevention and treatment. In our research, we explored semi-synthetic derivatives of cycloastragenol (CA) and astragenol (AG) to assess their potential to inhibit inflammation-mediated tumorigenic signaling. Building on our previous findings, which demonstrated their inhibitory activity on NFκB, we discovered that these molecules also suppress inflammation-induced cell proliferation and migration through distinct mechanisms. They effectively alleviated inflammation by reducing levels of ROS, NO, and VEGF expression. Furthermore, these molecules partially restored the expression of AR and the tumor suppressor NKX3.1, both of which are critical in prostate tumorigenesis within an inflammatory microenvironment. They also reversed inflammation-induced activation of Akt and β-catenin signaling, suggesting their potential to inhibit inflammation-related prostate tumorigenesis. Our study further demonstrated that these molecules exhibited dose-dependent effects on inducing cell cycle arrest and apoptosis, as evidenced by increased p21 and decreased BCL-2 protein levels, leading to activated cell death and suppressed cellular migration. In conclusion, these semi-synthetic sapogenol derivatives demonstrate significant potential as anti-inflammatory and anticancer agents, offering a promising approach for targeting prostatic inflammation and inflammation-driven prostate carcinogenesis.
    Keywords:  Astragenol; Cycloastragenol; Inflammation-induced tumorigenesis; Prostate cancer; β-catenin
    DOI:  https://doi.org/10.1016/j.steroids.2025.109723
  33. Curr Issues Mol Biol. 2025 Oct 30. pii: 902. [Epub ahead of print]47(11):
    Combination Treatment of Carboxyl Esterase 2-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhances the Inhibition of Tumor Growth by Irinotecan in PC3, a Castration-Resistant Prostate Cancer Model.
    Jae Heon Kim, Miho Song, Jeongkun Lee, Sang Hun Lee, Yun Seob Song.
      Castration-resistant prostate cancer (CRPC) remains difficult to treat with conventional chemotherapy. We evaluated a stem cell-based enzyme-prodrug strategy using hTERT-immortalized adipose-derived stem cells engineered to express rabbit carboxylesterase 2 (hTERT-ADSC.CE2) in combination with irinotecan (CPT-11). hTERT-ADSC.CE2 cells were generated via lentiviral transduction and confirmed to overexpress CE2. Their tumor-homing capacity toward PC3 prostate cancer cells was assessed, along with prodrug activation, apoptosis induction, and in vivo tumor suppression in a CRPC mouse model. hTERT-ADSC.CE2 cells demonstrated enhanced migration toward PC3 cells and higher expression of tumor-homing factors than the controls. Under CPT-11, they exhibited a strong "suicide" effect and induced selective killing of PC3 cells, with upregulation of BAX and cleaved caspase-3 and downregulation of BCL-2. By day 14, the combination arm showed significantly lower tumor burden than both the control and irinotecan-alone arms (p < 0.05). The pattern is consistent with intratumoral activation and localized SN-38 exposure. hTERT-ADSC.CE2 combined with irinotecan provides potent, tumor-targeted cytotoxicity and markedly suppresses CRPC progression. This cell-mediated prodrug activation system may represent a promising therapeutic approach for advanced prostate cancer.
    Keywords:  carboxylesterase; prostate cancer; stem cells
    DOI:  https://doi.org/10.3390/cimb47110902
  34. Curr Comput Aided Drug Des. 2025 Nov 21.
    A Pharmacoinformatics and Molecular Dynamics Approach to the Phytochemical Screening of Ficus hispida Fruits for Prostate Cancer Therapy.
    Hasanur Rahman, Ataur Rahman, Sarwar Zahan, Partha Biswas, Abdullah Al Mamun Sohag, Silme Islam, Riyan Al Islam Reshad, Bablu Gupta, Redwanul Islam, Abdul Hannan, Abdel Halim Harrath, Woojin Kim, Jamal Uddin, Bonglee Kim.
       INTRODUCTION: Prostate cancer is one of the most prevalent malignancies and a leading cause of cancer-related deaths among men. The androgen receptor (AR) plays a pivotal role in the development and progression of prostate cancer, making it a promising therapeutic target. This study aimed to evaluate the therapeutic potential of phytochemicals derived from the fruit of Ficus hispida in inhibiting the androgen receptor (PDB ID: 5T8E), thereby contributing to the treatment of prostate cancer.
    METHODS: Phytochemicals from Ficus hispida fruit were screened using molecular docking to assess their binding affinity to the androgen receptor. Subsequently, ADMET profiling and PASS online predictions were used to evaluate drug-likeness and anticancer potential. Molecular dynamics (MD) simulations (100 ns) were conducted to confirm the binding stability of the top candidates with the target protein.
    RESULTS: Five phytochemicals, Nodakenetin (CID: 26305), Isowigtheone hydrate (CID: 66728267), Methyl chlorogenate (CID: 6476139), 7-Hydroxycoumarin (CID: 5281426), and Gallic acid (CID: 370), were identified with high binding affinity and favorable binding free energy. The 100-ns MD simulations validated the structural stability of these phytochemical- AR complexes, indicating strong and stable interactions.
    CONCLUSION: The identified phytochemicals from Ficus hispida demonstrate significant potential to inhibit androgen receptor activity and could serve as promising candidates for developing therapeutic agents against prostate cancer.
    Keywords:  ADME; Ficus hispida; anti-cancer therapeutics.; molecular dynamics; prostate cancer
    DOI:  https://doi.org/10.2174/0115734099409352251103111907
  35. Clin Exp Med. 2025 Nov 26.
    Tumor microenvironment-mediated immune evasion and resistance in prostate cancer: mechanisms, cross-talk, and therapeutic opportunities.
    Mingfeng Li, Louis Boafo Kwantwi, Cuimei Wang, Qin Xiao.
      Prostate cancer (PCa) remains one of the leading causes of cancer-related morbidity and mortality in men worldwide, and therapeutic resistance-particularly to immunotherapy-continues to limit clinical efficacy. Mounting evidence has positioned the immunosuppressive tumor microenvironment (TME) as a core driver of disease progression and a formidable barrier to effective immune-based interventions. In this review, we present a comprehensive and multi-dimensional analysis of the cellular, stromal, and molecular constituents of the immunosuppressive TME in PCa, highlighting its significant heterogeneity and context-dependent functions. We emphasize recent breakthrough insights obtained through single-cell RNA sequencing (scRNA-seq), spatial multi-omics, and high-dimensional imaging technologies, which are redefining our understanding of tumor-immune-stromal interactions. Based on these mechanistic findings, we examine precision therapeutic strategies aimed at remodeling the TME, including combinatorial immune checkpoint blockade, metabolic reprogramming, cytokine network regulation, and advanced nanomedicine-based delivery systems. Finally, we discuss translational opportunities and future research directions, underscoring the necessity of integrating advanced omics technologies with biomarker-driven clinical trial design to enable individualized, precision interventions and improve survival outcomes for patients with PCa.
    Keywords:  Cell therapy; Immune checkpoint; Immunosuppression; Precision therapy; Prostate cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10238-025-01944-0
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