bims-meproc 2025-11-23 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–11–23
28 papers selected by
Grigor Varuzhanyan, UCLA

GLP1 Receptor Agonism Alters Growth and Therapeutic Response in Prostate Cancer.
Metabolic subtyping reveals PDIK1L as a dual-functional regulator of progression and PARP inhibitor sensitivity in prostate cancer.
Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression.
Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.
ETS-related gene as a key factor in curcumin inhibition of glucose metabolism in prostate cancer cells: an in vitro experimental study.
WSB1 promotes prostate cancer malignancy through OTUD4-mediated ISOC2 stabilization and P16INK4a suppression.
Proteomics of Prostate Cancer Tissue Small Extracellular Vesicles Reveal Alteration of Metabolism.
PTEN deficiency impairs IL-15-dependent T-cell immunity against prostate cancer.
Rho kinase 2 promotes epithelial-mesenchymal transition and proliferation in human prostate cancer PC-3 cells.
Prediction of bone or lung metastasis in prostate cancer using machine learning: a SEER-based study with external validation.
A newly synthesized compound induces apoptosis in prostate cancer cells by targeting mitochondrial dysfunction and the TP53/BCL-2/SEMA3 pathways.
The intricate interplay between circadian rhythm, androgen signaling, hormone therapy, and cellular senescence in prostate cancer.
Integrative analysis reveals SRD5A2 as a central mediator in PPCPs induced modulation of the prostate cancer immune microenvironment.
The ubiquitin ligase RCBTB2 regulates aggrephagy and inhibits prostate cancer progression by targeting GPAA1 for degradation.
Transcriptional network analysis of PTEN-protein-deficient prostate tumors reveals robust stromal reprogramming and signs of senescent paracrine communication.
Multi-omics analysis indicates an association between TAPBP and prostate cancer.
A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization.
Prognostic and immune microenvironment of a cancer-associated fibroblast-related genes signature for biochemical recurrence in prostate cancer.
GRPR-induced FAM135A expression promote perineural invasion in prostate cancer.
Editorial Comment on Androgen Receptor Signaling Inhibitors in Nonmetastatic Castration-Resistant Prostate Cancer in Japan: The ARASHI Study.
Generation of Rat Monoclonal Antibodies for Human and Mouse Androgen Receptor.
DGAT1 as a Racially Divergent Driver of Carcinoma-Associated Fibroblast Activation Drives Tumorigenic Pathways via ERK1/2 Signaling in Prostate Cancer.
EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.
High hyaluronan binding and RHAMM expression identify an invasive and metastatic subpopulation in androgen-resistant prostate cancer cells.
Expression and diagnostic potential of circulating miR-107, miR-134-5p, miR-149-5p, miR-370-3p, and miR-221 in prostate cancer and benign prostatic hyperplasia: a preliminary study.
Long-Term Follow-Up of Neoadjuvant Enzalutamide Plus Androgen Deprivation Therapy in Localized Prostate Cancer: A Secondary Analysis of a Neoadjuvant Feasibility Trial.
Spatial multi-omics identifies aggressive prostate cancer signatures highlighting pro-inflammatory chemokine activity in the tumor microenvironment.
Testosterone Replacement in Prostate Carcinoma: A Systematic Review of an Emerging Paradigm and Therapeutic Potential.

Endocr Relat Cancer. 2025 Nov 19. pii: ERC-25-0185. [Epub ahead of print]

GLP1 Receptor Agonism Alters Growth and Therapeutic Response in Prostate Cancer.

Soumen Bera, Lisa Gutgesell, Brynne Darden, Robert M Sargis, Mark Maienschein-Cline, Charles E Gaber, Natalie Reizine, Donald J Vander Griend, Jordan E Vellky.

  The burgeoning metabolic benefits of GLP1 receptor (GLP1R) agonists have led to their widespread use for treatment of type 2 diabetes mellitus and obesity. While the pharmacological GLP1R agonist semaglutide primarily activates GLP1R signaling in the pancreas, GLP1R is also expressed in advanced prostate cancer where GLP1R agonism could directly alter cellular signaling. Because metabolic disorders and their treatment are common among those with prostate cancer, understanding the effects of semaglutide in prostate cells is critical for deciphering its systemic effects and delineating potential impacts on prostate cancer outcomes. In prostate cancer models, semaglutide decreased cell proliferation, glycolytic function, and phospho-kinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with inhibitory GPCR signaling, which was confirmed by reduced cAMP levels. Further, cell proliferation was decreased with semaglutide alone and in combination with enzalutamide, supporting that GLP1R agonism may provide therapeutic benefit as a standalone treatment or to augment the therapeutic benefits of androgen receptor signaling inhibitors (ARSI). Interestingly, in a trans-differentiation model (n=55), GLP1R and AR expression were negatively correlated, while GLP1R and NEPC markers (DLL3, ASCL1) were positively correlated, suggesting an association between GLP1R and neuroendocrine differentiation. Bioinformatic analyses on publicly-available patient RNA-sequencing data (n=664) identified significantly higher GLP1R expression in advanced prostate cancer vs. benign prostate, where it was associated with negative Notch signaling. Taken together, our data support a model wherein GLP1R agonism blocks oncogenic signaling pathways and growth of prostate cancer cells that could be exploited therapeutically for men with advanced prostate cancer.

Keywords:  Castration-resistant prostate cancer; Neuroendocrine prostate cancer; advanced prostate cancer; incretin mimetics; metabolic co-morbidities

DOI:  https://doi.org/10.1530/ERC-25-0185
Front Cell Dev Biol. 2025 ;13 1674844

Metabolic subtyping reveals PDIK1L as a dual-functional regulator of progression and PARP inhibitor sensitivity in prostate cancer.

Zhongyuan Wang, Qintao Ge, Anwaier Aihetaimujiang, Ji Zhang, Jiahe Lu, Jianfeng Yang, Yonghao Chen, Bin Qin, Hailiang Zhang, Wen-Hao Xu, Dingwei Ye.

   Background: Prostate cancer demonstrates significant metabolic heterogeneity, but its role in therapeutic resistance and disease progression remains unclear. This study investigates the clinical implications of metabolic diversity and identifies potential biomarkers for precision oncology.
Methods: Multi-omics analyses of TCGA-PRAD and meta-cohorts classified tumors into three metabolic subtypes (C1, C2, C3). Functional studies utilized prostate cancer cell lines with genetic modulation of PDIK1L. Proliferation assays, protein expression analysis, and drug sensitivity evaluations were systematically performed.
Results: Metabolic subtyping delineated distinct molecular and clinical profiles. The C2 subtype demonstrated elevated genomic instability and heightened sensitivity to PARP inhibitors, characterized by enrichment of glycogen metabolism and TP53-driven oncogenic pathways. Integrative multi-omics and random survival forest analysis prioritized PDIK1L as a C2-specific biomarker, where its overexpression accelerated tumor proliferation and rewired metabolic programs to confer resistance to PARP inhibitors. Conversely, PDIK1L knockdown suppressed proliferation and sensitized cells to therapy, underscoring its role as a dual-functional regulator. Mechanistically, PDIK1L interacted with DNA repair and metabolic adaptation pathways, creating a permissive environment for therapeutic resistance. Combinatorial therapy with Enzalutamide and PARP inhibitors effectively reversed PDIK1L-mediated resistance, restoring drug sensitivity across preclinical models. Independent validation in multi-institutional cohorts confirmed the robustness of metabolic subtyping and PDIK1L's prognostic value in predicting survival and treatment outcomes.
Discussion: Metabolic stratification reveals the C2 subtype as a high-risk prostate cancer group with unique therapeutic vulnerabilities. PDIK1L emerges as a dual-functional biomarker driving tumor progression and modulating treatment efficacy, offering a novel target for precision therapeutic strategies.

Keywords:  PARP inhibitor; durg resistance; genomic instability; metabolic subtyping; prostate cancer

DOI:  https://doi.org/10.3389/fcell.2025.1674844
Mol Biomed. 2025 Nov 17. 6(1): 112

Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression.

Haoran Wen, Maierhaba Maheremu, Kaidi Zhang, Liuru Bao, Mayao Luo, Yifan Zhang, Yuanpeng Liao, Manli Zhou, Chenwei Wu, Shidong Lv, Xiaofu Qiu, Qiang Wei.

  Castration-resistant prostate cancer (CRPC) poses a significant clinical challenge, characterized by limited therapeutic options and unfavorable prognosis, particularly among elderly men. Reactivation of androgen receptor (AR) signaling remains the principal driver of CRPC cell survival and tumor progression even under castrated levels of serum androgen. Lysine methyltransferase 2D (KMT2D) has been established as a key oncogenic driver in prostate cancer, promoting tumor progression via multiple pathways. However, its functional interaction with the AR signaling axis in the context of CRPC remains incompletely understood. In this study, we demonstrate that KMT2D substantially upregulates AR protein levels, thereby reactivating AR signaling under castration conditions. Mechanistically, KMT2D employs its histone methyltransferase function to transcriptionally enhance the expression of G3BP stress granule assembly factor 1 (G3BP1). Upregulated G3BP1 subsequently suppresses the activity of the E3 ubiquitin ligase Speckle Type BTB/POZ protein (SPOP), leading to diminished AR ubiquitination and impaired proteasomal degradation. Furthermore, we explored a novel combination therapy involving the histone methyltransferase inhibitor MI-503 and enzalutamide in AR-positive and AR splice variant-positive cell lines. Our results confirmed the synergistic therapeutic effects of this combination, which can continue to inhibit the AR signaling pathway during the CRPC stage, thereby delaying disease progression. Taken together, our findings elucidate a critical KMT2D/G3BP1/SPOP/AR regulatory axis in prostate cancer progression and propose that targeted inhibition of histone methylation in combination with anti-androgen therapy represents a promising strategy for the management of advanced prostate cancer.

Keywords:  Androgen receptor; Castration-resistant; Methylation; Signaling; Ubiquitination

DOI:  https://doi.org/10.1186/s43556-025-00354-8
Cancer Res. 2025 Nov 21.

Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer.

Rajendra Kumar, Sheila Jonnatan, David E Sanin, Varsha Vakkala, Anoushka Kadam, Shivani Kumar, D Marc Rosen, Susan L Dalrymple, Liang Zhao, Jackson R Foley, Cassandra E Holbert, Ashley Nwafor, Srushti Kittane, Elizabeth Penner, Petya Apostolova, Samuel Warner, Chi V Dang, Eneda Toska, Elizabeth A Thompson, John T Isaacs, Angelo M De Marzo, W Nathaniel Brennen, Erika L Pearce, Tracy Murray Stewart, Robert A Casero, Samuel R Denmeade, Laura A Sena.

Supraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. AR binding at enhancer sites upstream of the ODC1 promoter increased the abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhanced prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation of ODC1 or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, AR activation combined with loss of negative feedback by polyamines increased the activity of S-adenosylmethionine decarboxylase 1 (AMD1), leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this therapeutic combination in the first five patients on trial indicated that this approach effectively depleted polyamines in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1532
J Yeungnam Med Sci. 2025 ;42 78

ETS-related gene as a key factor in curcumin inhibition of glucose metabolism in prostate cancer cells: an in vitro experimental study.

Yunye Wang, Xingyu Zhao, Jierui Zhao, Xin Wang, Yumiao Guo, Shutong Chen, Ying Jin, Peng Peng, Wei Zhang.

   BACKGROUND: Curcumin, the main yellow pigment in turmeric, is a potent anticancer agent. However, its effect on the viability of human prostate cancer (PCa) cells and underlying mechanisms remain unclear. This study aimed to determine the effects of curcumin on the proliferation and glucose metabolism of PCa cells.
METHODS: Cell viability was measured by MTS assay, and apoptosis was measured by flow cytometry. Glucose metabolism was assessed by measuring glucose intake, lactate production, and adenosine triphosphate content. Western blotting was performed to detect the expression of apoptosis-related proteins.
RESULTS: Curcumin treatment significantly reduced the viability of two types of PCa cells. We also found that curcumin increased apoptosis and glycolysis by inhibiting the activities of phosphatidylinositol 3-kinase/protein kinase B and hypoxia-inducible factor-1α. Furthermore, curcumin reduced the expression of ETS-related gene (ERG). However, after the ERG was knocked out, the effects of curcumin treatment were attenuated.
CONCLUSION: This study investigated the effects of curcumin on the proliferation and apoptosis of PCa cells, which may be related to the inhibition of glycolysis, and further explored the pathway involved. The subsequent effect on ERG expression indicated that these effects may be related to this oncogene.

Keywords:  Apoptosis; Curcumin; ERG; Glycolysis; Prostatic neoplasms

DOI:  https://doi.org/10.12701/jyms.2025.42.78
Am J Cancer Res. 2025 ;15(10): 4434-4451

WSB1 promotes prostate cancer malignancy through OTUD4-mediated ISOC2 stabilization and P16INK4a suppression.

Jian Sun, Fei Wang, Yuxuan Feng, Xiya Qiu, Wenying Qu, Xuefeng He, Jianjun Xie, Gang Li.

  Polyubiquitination plays a critical role in tumor biology, yet its significance in prostate cancer remains incompletely understood. Here, we investigated the expression and function of SOCS-box E3 ligases in prostate cancer. Analysis of TCGA data revealed WSB1 overexpression, which correlated with advanced pathological stage, high Gleason score, and poor prognosis. Functional assays demonstrated that WSB1 knockdown suppressed prostate cancer cell proliferation, colony formation, and migration in vitro, and inhibited tumor growth and Ki67 expression in vivo. Mechanistically, mass spectrometry and co-immunoprecipitation identified ISOC2 as a key WSB1 interactor. WSB1 stabilized ISOC2 by promoting its interaction with the deubiquitinase OTUD4, thereby preventing ISOC2 degradation via the ubiquitin-proteasome pathway. Silencing either ISOC2 or OTUD4 phenocopied the tumor-suppressive effects of WSB1 ablation. Importantly, disruption of the WSB1/OTUD4/ISOC2 axis upregulated P16INK4a expression, and co-silencing of P16INK4a partially restored tumorigenic properties. Our findings unveil a novel WSB1/OTUD4/ISOC2 signaling network that drives prostate cancer progression by modulating ubiquitin signaling and repressing P16INK4a, positioning WSB1 as a promising therapeutic target.

Keywords:  ISOC2; OTUD4; WSB1; prostate cancer; ubiquitination

DOI:  https://doi.org/10.62347/HGMA4543
Proteomics. 2025 Nov 17. e70081

Proteomics of Prostate Cancer Tissue Small Extracellular Vesicles Reveal Alteration of Metabolism.

Lijuan Yu, Ting Ding, Roger Olofsson Bagge, Lei Zheng, Xiaoke Hao.

  Prostate cancer (PCa) is a leading male malignancy worldwide, with metabolic reprogramming being a critical hallmark of its progression. Extracellular vesicles (EVs) derived from tissues directly reflect the tumor microenvironment, offering unique insights into cancer pathophysiology that are unattainable through cell line or biofluid-derived EVs. However, the functional roles of tissue-derived EVs in PCa metabolism remain poorly understood. Leveraging our expertise in murine PCa model establishment and EV isolation from prostate tissue, this study aimed to characterize functional differences between PCa and normal prostate tissue via proteomic analysis of tissue-derived sEVs. We orthotopically implanted luciferase-labeled PCa cells into nude mice to establish an in situ PCa model, confirmed tumor formation via in vivo imaging, and harvested tissues after 4 weeks. sEVs were isolated using ultracentrifugation combined with an iodixanol density cushion and characterized by transmission electron microscopy, nanoparticle tracking analysis, and protein marker profiling. Proteomic analysis identified 28 upregulated and 24 downregulated proteins in PCa-derived sEVs compared to normal controls. Subcellular localization revealed enrichment in the cytoplasm, while pathway analysis highlighted significant involvement in metabolic processes, particularly glycolysis, amino acid biogenesis, carbon metabolism, and pyruvate metabolism. Our study establishes a robust method for isolating prostate tissue sEVs and provides the first evidence that PCa tissue-derived sEVs exhibit profound metabolic pathway alterations. These findings enhance our understanding of PCa progression mechanisms and may facilitate the development of novel diagnostic biomarkers and therapeutic strategies targeting metabolic dysregulation in PCa. SUMMARY: In this study, we created a method to isolate prostate tissue small EVs, based on our knowledge of the murine prostate cancer model building. Our data suggested that prostate tissue small EVs proteins significantly changed in many metabolism pathways, such as Glycolysis, Biogenesis of amino acids, Carbon metabolism and Pyruvate metabolism. In this study, we are the first to report prostate tissue-derived EVs proteins enriched in alterations of cancer metabolism. These differential proteins in PCa tissue EVs reflect metabolic changes in PCa and may provide insights into the development of early diagnostic biomarkers or novel therapeutic strategies.

Keywords:  Glycolysis; prostate cancer; tissue EVs; tumor metabolism

DOI:  https://doi.org/10.1002/pmic.70081
Biochem Biophys Res Commun. 2025 Nov 12. pii: S0006-291X(25)01688-2. [Epub ahead of print]792 152972

PTEN deficiency impairs IL-15-dependent T-cell immunity against prostate cancer.

Yujie Xing, Zixuan Zeng, Chi Wang, Yuchen Qian, Zhuang Chen, Wenyue Huang, Mengxi Huan, Yalong Wang, Yang Gao.

  Prostate cancer (PCa) is widely recognized as an immunologically "cold" tumor that responds poorly to immunotherapy, largely due to its poorly infiltrated immune microenvironment. Genetic loss or functional inactivation of phosphatase and tensin homolog (PTEN) is a well-established driver of PCa tumorigenesis and progression. However, the mechanisms by which PTEN-deficiency shapes the tumor immune landscape, particularly T cell infiltration and activity, remain poorly understood. Here, we report that PTEN deficiency is associated with reduced T-cell infiltration in human PCa tissues. CRISPR/Cas9-mediated knockout (KO) of Pten in murine syngeneic tumor models similarly results in diminished intratumoral CD8+ T cell accumulation. Mechanistically, loss of PTEN suppresses IL-15 production by impairing activation of the cGAS-STING signaling pathway. Restoration of IL-15 in Pten KO PCa cells reinvigorates antitumor immunity and promotes T-cell infiltration within the tumor microenvironment. Together, our findings identify PTEN as a critical regulator of IL-15-associated T-cell immunity and suggest that IL-15-based therapeutic strategies may offer a promising approach for PTEN-deficient PCa.

Keywords:  IL-15; Immune microenvironment; PTEN; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbrc.2025.152972
J Pharmacol Sci. 2025 Dec;pii: S1347-8613(25)00093-3. [Epub ahead of print]159(4): 229-241

Rho kinase 2 promotes epithelial-mesenchymal transition and proliferation in human prostate cancer PC-3 cells.

Alamgir Hossain, Aya Yamamura, Md Junayed Nayeem, Sivasundaram Karnan, Rie Takahashi, Hisaki Hayashi, Motohiko Sato.

  Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC50 = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.

Keywords:  Epithelial-mesenchymal transition; KD025; PC-3; Prostate cancer; ROCK2

DOI:  https://doi.org/10.1016/j.jphs.2025.09.007
Discov Oncol. 2025 Nov 19.

Prediction of bone or lung metastasis in prostate cancer using machine learning: a SEER-based study with external validation.

Mingyan Zhong, Ru Chen.



Keywords:  Bone metastasis; Lung metastasis; Machine learning prediction; Prostate cancer metastasis

DOI:  https://doi.org/10.1007/s12672-025-04030-9
Biochem Biophys Res Commun. 2025 Nov 16. pii: S0006-291X(25)01696-1. [Epub ahead of print]792 152980

A newly synthesized compound induces apoptosis in prostate cancer cells by targeting mitochondrial dysfunction and the TP53/BCL-2/SEMA3 pathways.

Neslihan Meriç, Ezgi Kar, Fatih Kar.

  Recent investigations have emphasized the therapeutic potential of thiazole derivatives in oncology. In this study, the novel compound 2-[(4,5-dihydrothiazol-2-yl)thio]-N-(4-methylthiazol-2-yl)acetamide was evaluated for its cytotoxic and mechanistic effects on PC-3 prostate cancer cells. Cell viability decreased significantly after treatment (∗∗∗∗p ≤ 0.0001), and HEK-293 cells showed relative resistance at lower doses. Annexin V/PI flow cytometry revealed a dose-dependent increase in apoptosis, most pronounced at 88 μM (∗∗∗∗p < 0.0001), and JC-1 assays confirmed membrane depolarization (∗∗∗∗p < 0.0001). RT-qPCR analysis revealed significant downregulation of PSA and c-MYC (∗∗∗∗p < 0.0001) with a mild increase in TP53 expression. ELISA-based protein quantification showed elevated Caspase-3 and a biphasic modulation of Cytochrome-c, supporting activation of intrinsic apoptosis. GPX4 levels remained largely unchanged except at 128 μM, and SEMA3A expression was not significantly affected. Among inflammatory cytokines, TNF-α levels increased dose-dependently (∗∗∗∗p < 0.0001), while IL-6 and IL-10 showed no significant alterations. Collectively, These findings indicate that the synthesized thiazole compound exerts selective cytotoxicity toward prostate cancer cells via mitochondria-mediated apoptosis and inflammatory signaling modulation.

Keywords:  4-Methylthiazole; Apoptosis; Cell cycle; Inflammatory signaling; Mitochondrial dysfunction; PC-3 cells; SEMA3A

DOI:  https://doi.org/10.1016/j.bbrc.2025.152980
Cancer Metastasis Rev. 2025 Nov 20. 44(4): 84

The intricate interplay between circadian rhythm, androgen signaling, hormone therapy, and cellular senescence in prostate cancer.

Mehdi Heidari Horestani, Aria Baniahmad.

  Prostate cancer (PCa) is the second most diagnosed cancer and the fifth leading cause of cancer death among men worldwide. Androgen receptor (AR), as a ligand-activated transcription factor, is important for both prostate development and PCa progression. Understanding the molecular mechanisms of prostate carcinogenesis has led to the development of therapeutic strategies targeting AR. Inhibiting AR is currently the gold standard for hormone therapy. However, eventually resistance to therapy occurs. The activation of AR by supraphysiological androgen levels (SAL) used currently in clinical trials paradoxically also inhibits PCa progression and induces cellular senescence. Interestingly, circadian rhythm controls hormone biosynthesis including androgens. Intriguingly, SNPs in several clock genes have been associated with PCa risk linking increased cancer risk with day-night shifts. Here, we discuss whether the efficacy of hormone therapeutics depends on the biological clock. It emerges that androgens control the expression of clock genes also intersecting with SAL-induced cellular senescence suggesting a complex and understudied network that governs PCa progression. This review highlights the multifaceted roles of AR signaling in PCa, emphasizing its ability to promote cellular senescence by AR-targeted therapy via genomic and non-genomic pathways and crosstalk with the regulation of circadian clock genes. The intricate interplay between circadian rhythm, androgen signaling, and cellular senescence presents a promising yet underexplored research area in PCa and suggests a multilayered regulatory network that could shape PCa progression and treatment outcomes. Unraveling this network may uncover novel chronotherapeutic strategies and provide new insights into disease, prognosis, and therapy options.

Keywords:  Androgen receptor; Cancer; Cellular senescence; Circadian rhythm; Clock genes; Prostate cancer

DOI:  https://doi.org/10.1007/s10555-025-10302-1
Discov Oncol. 2025 Nov 21. 16(1): 2141

Integrative analysis reveals SRD5A2 as a central mediator in PPCPs induced modulation of the prostate cancer immune microenvironment.

Tao Zhou, Yuqi Li, Peng Ji, Chunyang Meng, Zhiyu Liu, Zhiqiang Zeng, Yuming Yang, Tao Li.

   BACKGROUND: Pharmaceuticals and Personal Care Products (PPCPs) are an emerging class of micropollutants that have attracted increasing attention in recent years. However, their potential role in prostate cancer (PCa) remains largely unexplored. This study aims to elucidate the mechanisms by which PPCPs influence PCa progression and identify key genes involved in this process.
METHODS: A network toxicology approach was employed to identify PPCPs related genes associated with PCa. Bioinformatics analyses were conducted to pinpoint key genes and their underlying mechanisms. Additionally, molecular docking was performed to assess the binding affinity between PPCPs and the identified genes.
RESULTS: The study analyzed the relationship between 49 types of PPCPs and PCa, ultimately identifying 24 types of PPCPs that may promote the development of PCa. Network toxicology analysis identified 156 PPCPs-PCa related genes. Further screening using univariate Cox regression analysis, clinical correlation analysis, and Lasso prognostic modeling revealed four prognostic genes closely linked to PCa outcomes. Molecular docking demonstrated strong binding affinities between these genes and the 24 PPCPs, with SRD5A2 exhibiting the highest binding affinity. Moreover, immune infiltration analysis indicated a significant correlation between SRD5A2 and the tumor immune microenvironment (TIME).
CONCLUSION: The genes F2, SRD5A2, NEK2, and HGFAC play critical roles in PPCPs induced PCa progression, with SRD5A2 being particularly significant. These findings suggest that PPCPs may disrupt TIME homeostasis by downregulating SRD5A2 expression, thereby promoting immune evasion of PCa cells and accelerating tumor progression.

Keywords:  Immune infiltration; Molecular docking; Network toxicology; Pharmaceuticals and personal care products; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-03995-x
Am J Cancer Res. 2025 ;15(10): 4245-4263

The ubiquitin ligase RCBTB2 regulates aggrephagy and inhibits prostate cancer progression by targeting GPAA1 for degradation.

Ren Mo, Ning Chi, Jianjun Du, Xinhua Li, Weihang Guo, Haozhe Li, Jiawei Wang, Chuanhai Cai, Sanxiang Li, Chunxiao Liu.

   BACKGROUND: Prostate cancer (PCa) ranks among the most prevalent malignant tumors affecting the male genitourinary system, presenting a considerable danger to health and human life. Increasing evidence indicates that the ubiquitin-proteasome pathway is essential in both the development and management of PCa.
METHODS: Differential expressed genes were screened by integrating the TCGA and GEO databases, and their expression was validated in the HPA dataset. An RCBTB2 overexpression cell line was constructed, and its effects on cellular behavior were analyzed using CCK-8, scratch assay, Transwell, and immunofluorescence staining. A nude mouse model was established to evaluate the tumor-suppressive effects. Furthermore, the interaction between RCBTB2 and GPAA1 was confirmed through multi-omics analysis, co-immunoprecipitation, and immunofluorescence co-localization experiments. GPAA1 knockdown cell lines were then constructed to observe changes in cellular phenotypes.
RESULTS: The expression of RCBTB2 was significantly negatively correlated with the malignancy of PCa. Overexpression of RCBTB2 notably inhibited DU145 cell proliferation, migration, invasion, and EMT, as well as reduced the growth of xenograft tumors in nude mice. Multi-omics analysis revealed that RCBTB2 promoted the ubiquitin-mediated degradation of GPAA1 (protein downregulation without changes in mRNA levels), and experiments confirmed their direct interaction. Furthermore, GPAA1 knockdown suppressed the malignant biological behaviors of PCa cells and reduced the expression of aggrephagy-related factors such as p62.
CONCLUSION: This study for the first time unveils the molecular mechanism by which RCBTB2 inhibits PCa progression through ubiquitination-mediated degradation of GPAA1. It provides a novel target for protein homeostasis-based therapy, with promising clinical value.

Keywords:  GPAA1; Prostate cancer; RCBTB2; ubiquitination

DOI:  https://doi.org/10.62347/XKCS2457
Mol Oncol. 2025 Nov 17.

Transcriptional network analysis of PTEN-protein-deficient prostate tumors reveals robust stromal reprogramming and signs of senescent paracrine communication.

Ivana Rondon-Lorefice, Jose I Lopez, Aitziber Ugalde-Olano, Maite Zufiaurre, Ianire Astobiza, Natalia Martin-Martin, Laura Bozal-Basterra, Saioa Garcia-Longarte, Amaia Zabala-Letona, Sofia Rey, Aida Santos-Martin, Miguel Unda, Ana Loizaga-Iriarte, Mariona Graupera, Paolo Nuciforo, Arkaitz Carracedo, Isabel Mendizabal.

  Among the extensive genomic alterations in prostate cancer, phosphatase and tensin homolog (PTEN) deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated with cancer-cell proliferation and survival through the activation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mechanistic target of rapamycin (mTOR) (PI3K-AKT-mTOR) signaling pathway. However, the use of PTEN as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional and post-translational regulation. In situ protein assessment by immunohistochemistry (IHC) captures PTEN protein status, but it does not report on associated tumor microenvironment remodeling. Here, we undertook an approach that combined PTEN immunoreactivity analysis with high-throughput transcriptional analysis to gain insights into the downstream functional effects of PTEN protein loss in primary tumors. Our extensive bioinformatic analyses highlighted stromal remodeling as a prominent cancer cell-extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to Pten loss-driven murine prostate cancer, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced transforming growth factor beta (TGF-β) signaling and that is compatible with the secretome of PTEN-deficient senescent cancer cells. Finally, our findings enable the sub-stratification of tumors with PTEN loss based on their senescence-associated stroma remodeling program to distinguish indolent from aggressive cases. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss in prostate cancer.

Keywords:  PTEN protein loss; prostate cancer; stratification; stromal remodeling

DOI:  https://doi.org/10.1002/1878-0261.70164
PLoS One. 2025 ;20(11): e0336438

Multi-omics analysis indicates an association between TAPBP and prostate cancer.

Xinlong Wang, Aimin Jiang, Chao Li, Zhiyong Liu.

Prostate cancer is one of the most common malignant tumors among men worldwide, and surgery remains its mainstay of treatment. It is unclear how prostate cancer develops and what the most effective drug targets are for treating prostate cancer. Therefore, we sought to identify the genes responsible for prostate cancer. By integrating multidimensional and high-throughput data, proteome wide association studies (PWAS), transcriptome wide association studies (TWAS), single-cell sequencing, functional enrichment, Mendelian randomization (MR), and Bayesian co-localization analyses were used to screen for candidate genes that may contribute to prostate cancer and associate with clinical results of prostate cancer. Our comprehensive analysis showed that protein abundance of eight genes was associated with prostate cancer, four of which were validated at the transcriptome level. These 8 candidate genes (MSMB, PLG, CHMP2B, ATF6B, EGF, TAPBP, GAS1 and MMP7) were validated. After combining single-cell sequencing, Mendelian randomization, and Bayesian co-localization analyses, we identified 1 gene (TAPBP) that is strongly associated with prostate cancer.

DOI: https://doi.org/10.1371/journal.pone.0336438
Commun Chem. 2025 Nov 18. 8(1): 356

A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization.

Yuxin Fu, Longying Jiang, Guojian Xie, Yuchong Peng, Yongming Fu, Qianling Zhu, Youhong Liu, Guilong Zhao, Xueke Liu, Yongbo Peng, Yongheng Chen, Xiong Li.

UHRF1 is a pivotal epigenetic regulator bridging DNA methylation and histone modifications, frequently overexpressed in prostate cancer (PCa). However, no UHRF1-targeted therapeutics have advanced to clinical trials. Here, we report the development of H93, a hybrid small molecule integrating functional groups derived from NSC232003 and vorinostat, respectively. H93 exhibits potent anticancer activity in vitro, correlating with UHRF1 protein abundance, and co-crystallization studies confirm that H93 directly binding to the SRA domain of UHRF1. Intriguingly, H93 promotes UHRF1 dimerization, generating a defined binding pocket that stabilizes compound engagement and enhances druggability of UHRF1 as a non-kinase target. Dimerized UHRF1 adopts a "closed" conformation that disrupts its interaction with DNMT1, impairs DNA methylation maintenance, and reactivates epigenetically silenced tumor suppressor genes. In vivo, H93 demonstrates significant antitumor efficacy. Overall, this study elucidates the structural and mechanistic basis of H93, establishing it as a promising UHRF1-targeted therapy for PCa.

DOI: https://doi.org/10.1038/s42004-025-01744-3
Medicine (Baltimore). 2025 Oct 31. 104(44): e45451

Prognostic and immune microenvironment of a cancer-associated fibroblast-related genes signature for biochemical recurrence in prostate cancer.

Meng Zhang, Min Min, Pan Zhang, Lingxun Li, Weiyang He, Lingxin Wang.

  Prostate cancer (PCa) ranks among the most prevalent malignancies worldwide. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) play a crucial role in influencing tumor evolution and progression. To elucidate their prognostic significance, we extracted and integrated PCa data from The Cancer Genome Atlas and the GSE70768, GSE70769, and GSE116918 datasets. Differentially expressed CAF-related genes between normal and tumor tissues were identified, and their associations with CAF subtypes and clinicopathological characteristics were explored through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Based on these features, we constructed a CAF-related prognostic model using multivariate Cox and least absolute shrinkage and selection operator regression analyses. A 9-gene signature (LMCD1, CXCL2, UNC5B, THBS2, JAM3, PIGR, SCUBE2, SRD5A2, and PCGEM1) was identified to generate a CAFs score for predicting biochemical recurrence risk. Further analyses of the TME, genetic mutations, and drug sensitivity revealed that this signature was closely associated with tumor immunity and treatment response. Collectively, this model highlights the pivotal role of CAFs in shaping the TME and provides novel insights for prognostic prediction and therapeutic strategies in PCa.

Keywords:  China; Department of Urology; Mianyang; The Third People’s Hospital of Mianyang

DOI:  https://doi.org/10.1097/MD.0000000000045451
Mol Cancer. 2025 Nov 17. 24(1): 293

GRPR-induced FAM135A expression promote perineural invasion in prostate cancer.

Ning Zhang, Xiaohao Ruan, Siteng Chen, Ruofan Shi, Xiaoqun Yang, Yongle Zhan, Stacia Chun, Chi Yao, Salida Ali, Brian Sze-Ho Ho, Ada Tsui-Lin Ng, Richard Ky Lo, Rong Na.

  Perineural invasion (PNI) is an independent adverse prognostic marker for prostate cancer (PCa) metastasis. Gastrin releasing peptide receptor (GRPR) targeted imaging and therapeutics have entered clinical trials, while its role in PCa perineural invasion remains unclear. Here, we uncovered Family With Sequence Similarity 135 Member A ༈FAM135A༉a dominant PNI driver activated by GRPR in PCa. First, PNI-PCa tissue showed higher neuroactive ligand-receptor interaction activity, and with FAM135A being the most notable marker in PNI group. Then in-vitro experiments using a co-culture system of PCa cells (including AR-positive LNCaP and AR-negative DU145/PC3) showed that FAM135A silencing abrogated tumor malignancy and neural invasion. Moreover, in vivo PCa-Sciatic nerve invasion mouse model demonstrated FAM135A inhibition controls tumor growth and improves motor function. Interestingly, FAM135A is nucleus enriched and its nuclear translocation is mediated by protein cytoplasmic-nuclear transporter RAN. Mechanistically, RNA-Seq and ChIP-Seq analyses identified Teneurin Transmembrane Protein 3 (TENM3) as a transcriptional target of nFAM135A, and TENM3 plays an essential role in nFAM135A-induced cancer-nerve invasion. Notably, FAM135A is ultimately activated by Gastrin Releasing Peptide GRP and its receptor GRPR. Moreover, pharmacological GRPR inhibitor represses FAM135A expression via MED15 activation. Together, we unveil FAM135A as an oncodriver and biomarker of PCa perineural invasion, and provide a novel strategy for PCa innervation therapeutics.

Keywords:  FAM135A; GRPR; Perineural invasion; Prostate cancer; RAN

DOI:  https://doi.org/10.1186/s12943-025-02508-2
Int J Urol. 2025 Nov 17.

Editorial Comment on Androgen Receptor Signaling Inhibitors in Nonmetastatic Castration-Resistant Prostate Cancer in Japan: The ARASHI Study.

Akihito Hashizume.

DOI: https://doi.org/10.1111/iju.70262
Monoclon Antib Immunodiagn Immunother. 2025 Nov 19.

Generation of Rat Monoclonal Antibodies for Human and Mouse Androgen Receptor.

Momo Koike, Tomoka Kawabata, Norikazu Kiguchi, Yu Hatano, Kentaro Suzuki, Taro Tachibana, Chikako Yokoyama.

  Androgen receptor (AR) is activated by binding to androgens, which leads to nuclear translocation, dimerization, and binding to androgen response elements (AREs) to regulate gene transcription. AR is important in masculinization during mammalian development and is a major driver of tumor growth in prostate cancer, for which AR pathway inhibitors are the standard treatment. However, the mechanisms by which AR participates in these processes remain unclear. In this study, we describe rat monoclonal antibodies (mAbs) that were generated against human and mouse AR. These mAbs recognize endogenous AR and were shown to be effective in the immunofluorescence staining of human cell lines and mouse tissue sections and in immunoprecipitation experiments. We expect these mAbs to be useful for functional analyses of AR.

Keywords:  androgen receptor; human cancer cell line; monoclonal antibody; mouse tissue; prostate cancer

DOI:  https://doi.org/10.1177/21679436251398987
bioRxiv. 2025 Sep 30. pii: 2025.09.28.679062. [Epub ahead of print]

DGAT1 as a Racially Divergent Driver of Carcinoma-Associated Fibroblast Activation Drives Tumorigenic Pathways via ERK1/2 Signaling in Prostate Cancer.

Sathyavathi ChallaSivaKanaka, Mamatha Kakarla, Renee E Vickman, Yana Filipovich, Philip Fitchev, Md Maksudul Alam, Pooja Talaty, Brian T Helfand, David Price, Simon W Hayward, Susan E Crawford, Omar E Franco.

Background: The incidence of lethal prostate cancer (PCa) is disproportionately higher in African American (AA) men compared to Caucasian (Cau) men. Racial differences in lipid reprogramming have been implicated in PCa progression. Recent studies identified race-specific biological alterations in carcinoma-associated fibroblasts (CAF). Here, we demonstrate that lipid-laden CAF from AA patients (AA CAF ) exhibits enhanced pro-tumorigenic functions compared to CAF from Cau patients (Cau CAF ).
Methods: DGAT1-regulated genes in fibroblasts were identified by transcriptomic profiling, and their biological consequences were evaluated in vivo. Patient-derived CAF from AA and Cau men were examined to determine their molecular response to DGAT1 inhibition during tumorigenesis.
Results: Lipid droplet (LD) biogenesis analysis revealed DGAT1-dependent LD accumulation in AA CAF . DGAT1 overexpression in fibroblasts enhanced fibroblast activation protein (FAP1) expression and promoted in vivo tumorigenicity of cancer cells. Transcriptome and secretome profiling identified novel DGAT1-regulated genes associated with metabolism, cell-cell signaling, motility, and angiogenesis, largely mediated through the ERK1/2 pathway. Importantly, DGAT1 inhibition in patient-derived CAF elicited racially divergent regulation of pro-tumorigenic mediators, including BDNF, VEGF, and TSP1.
Conclusions: Our findings reveal elevated DGAT1 expression in AA CAF as a targetable enzymatic driver that enhances fibroblast activation and supports adaptation to a lipid-rich tumor microenvironment, thereby promoting tumorigenesis.

DOI: https://doi.org/10.1101/2025.09.28.679062
J Clin Invest. 2025 Nov 18. pii: e195840. [Epub ahead of print]

EZH2 crosstalk with RNA methylation promotes prostate cancer progression through modulation of m6A autoregulation pathway.

Yang Yi, Joshua Fry, Chaehyun Yum, Rui Wang, Siqi Wu, Sharath Narayan, Qi Liu, Xingxing Zhang, Htoo Zarni Oo, Ning Xie, Yanqiang Li, Xinlei Gao, Xufen Yu, Xiaoping Hu, Qiaqia Li, Kemal Keseroglu, Ertuğrul M Özbudak, Sarki A Abdulkadir, Kaifu Chen, Jian Jin, Jonathan C Zhao, Xuesen Dong, Daniel Arango, Rendong Yang, Qi Cao.

  N6-methyladenosine (m6A), the most predominant RNA modification in humans, participates in various fundamental and pathological bioprocesses. Dynamic manipulation of m6A deposition in the transcriptome is critical for cancer progression, while how this regulation is achieved remains understudied. Here, we report that in prostate cancer (PCa), Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) exerts an additional function in m6A regulation via its enzymatic activity. Mechanistically, EZH2 methylates and stabilizes FOXA1 proteins from degradation, which in turn facilitates the transcription of m6A reader YTHDF1. Through activating an m6A autoregulation pathway, YTHDF1 enhances the translation of METTL14 and WTAP, two critical components of the m6A methyltransferase complex (MTC), and thereby upregulates the global m6A level in PCa cells. We further demonstrate that inhibiting the catalytic activity of EZH2 suppresses the translation process globally through targeting the YTHDF1-m6A axis. By disrupting both the expression and interaction of key m6A MTC subunits, combinational treatment of EZH2 degrader MS8815 and m6A inhibitor STM2457 mitigates prostate tumor growth synergistically. Together, our study decodes a previously hidden interrelationship between EZH2 and mRNA modification, which may be leveraged to advance the EZH2-targeting curative strategies in cancer.

Keywords:  Cell biology; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI195840
Matrix Biol. 2025 Nov 19. pii: S0945-053X(25)00110-6. [Epub ahead of print]

High hyaluronan binding and RHAMM expression identify an invasive and metastatic subpopulation in androgen-resistant prostate cancer cells.

Tolg C, Price M, Leith S, Miller T, Pavanel H, A C Nelson, Hill Ka, McCarthy Jb, Turley Ea.

  Hyaluronan (HA) metabolism in prostate cancer associates with androgen resistance and metastasis. We showed that binding of low molecular weight HA (≤250kDa) to castration-resistant prostate cancer cells was heterogeneous with most cells binding low amounts of HA (HAlow) while a minor subset bound higher amounts of this polysaccharide (HAhigh). HAhigh subsets, which were separated by FACS, were stably more metastatic in vivo than HAlow comparators. Multiplexed flow cytometry analyses indicated that both subsets displayed similar expression of the HA receptor CD44 while an elevated RHAMM cell surface display was unique to HAhigh subsets. Genomic deletion of RHAMM using CRISPR-Cas9 editing reduced the detection of HAhigh subsets by 6mer but not 250kDa HA fluorescent probes, and phenocopied the lower aggressive properties of HAlow tumor cells. Few differences in the mutation landscape of RHAMM+/+ vs. RHAMM-/- tumor cells were detected but pathway analyses of differentially expressed genes predicted RHAMM-loss altered extracellular matrix signaling. Transcriptomic analyses revealed that HAhigh subsets and RHAMM+/+ PC3MLN4 cells shared high expression of follistatin (FST), an activin member of the TGF-β family that is clinically linked to metastases in PCA patients. A causal role for FST in RHAMM+/+ tumor cell aggression was assessed using motility as a surrogate marker of invasive capability. FST antibodies blocked RHAMM+/+ PC3MLN4 cell migration while conversely, recombinant FST protein rescued the migration deficit of RHAMM-/- comparators. These results define a novel form of prostate cancer cell heterogeneity, identify a method for detecting and isolating highly metastatic subsets and highlight a novel RHAMM-regulated pathway that may be targeted to improve patient management by limiting metastasis.

Keywords:  Androgen resistant prostate cancer; Follistatin; RHAMM; hyaluronan; metastatic subset

DOI:  https://doi.org/10.1016/j.matbio.2025.11.006
Arch Ital Urol Androl. 2025 Nov 18. 14585

Expression and diagnostic potential of circulating miR-107, miR-134-5p, miR-149-5p, miR-370-3p, and miR-221 in prostate cancer and benign prostatic hyperplasia: a preliminary study.

Ali Akkoç, Hamiyet Eciroglu Sarban, Fatma Yildiz, Ozlem Ceren Gunizi, Murat Ucar.

BACKGROUND: MicroRNAs (miRNAs) have shown promise as diagnostic biomarkers for prostate cancer (PCa). This study aimed to evaluate the expression of miR-107, miR-134-5p, miR-149-5p, miR-370-3p, and miR-221 in whole blood to distinguish PCa from benign prostatic hyperplasia (BPH) and potentially reduce unnecessary biopsies.
METHODS: Whole blood samples were collected from 20 PCa patients, 17 histologically-confirmed BPH patients (all with PSA >4 ng/mL), and 20 healthy controls over 60 years without symptoms suggesting prostatic disease and PSA <4 ng/mL. miRNA levels were quantified using qRT-PCR. Diagnostic potential was assessed via correlation analyses with clinical parameters and ROC curve evaluation. Statistical significance was set at p<0.05.
RESULTS: miR-107, miR-134-5p, miR-149-5p, and miR-370-3p were significantly overexpressed in PCa patients compared to BPH (p<0.0001). ROC analysis identified miR-134-5p (AUC: 0.94) and miR-149-5p (AUC: 0.93) as strong predictors of PCa. Additionally, miR-149-5p showed a positive correlation with PSA levels (r = 0.2627, p<0.05).
CONCLUSIONS: This preliminary study demonstrated that miR-107, miR-134-5p, miR-149-5p, and miR-370-3p were significantly overexpressed in PCa patients compared to the BPH group. ROC analysis highlighted their diagnostic potential in distinguishing BPH from PCa. Despite the limited sample size, these findings provide early evidence to guide future research on the diagnostic value of miRNAs in prostate cancer.

DOI: https://doi.org/10.4081/aiua.2025.14585
Prostate. 2025 Nov 16.

Long-Term Follow-Up of Neoadjuvant Enzalutamide Plus Androgen Deprivation Therapy in Localized Prostate Cancer: A Secondary Analysis of a Neoadjuvant Feasibility Trial.

Braden Millan, Nikhil Pramod, Ruben Blachman-Braun, Jaskirat Saini, Lauren Loebach, Milan Patel, Sandeep Gurram, Baris Turkbey, Fatima Karzai, Peter A Pinto.

   INTRODUCTION: Neoadjuvant intense androgen deprivation therapy (ADT) with androgen receptor signaling inhibitors (ARSIs) has shown pathologic complete responses (pCR) in prostate cancer (PCa), but long-term survival outcomes remain unclear. This study evaluates the durability of response following neoadjuvant ADT plus enzalutamide before robot-assisted radical prostatectomy (RARP) and lymph node dissection.
METHODS: We conducted a secondary analysis of an open-label feasibility trial enrolling men with NCCN intermediate-, high-, very high-risk localized and regional PCa treated with 6 months of neoadjuvant ADT and enzalutamide. Factors associated with biochemical recurrence (BCR) and metastases were evaluated using appropriate univariable statistical tests, and BCR-, metastasis-free survival (MFS), and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method.
RESULTS: Of 39 patients enrolled, 36 patients completed all study interventions. Eighteen (66.7%) patients had NCCN very high-risk disease or clinical regional lymph nodes on imaging. Four patients (11.1%) achieved pCR, although two (5.6%) developed BCR. One patient (2.8%) had M1 and three (8.3%) had N1 disease on final pathology, and all four developed metastases. Eleven (30.6%) patients received salvage therapy, with all but one receiving ADT with radiation. Factors associated with BCR included biopsy ISUP grade and positive surgical margins, while NCCN risk group, biopsy ISUP grade, perineural invasion, and pathological stage were associated with metastases (p < 0.05). Median follow-up was 7.3 (95% CI 6.3-8.3) years, and the 5-year BCR-free survival, MFS, and CSS were 64.1%, 84.6%, and 94.3%, respectively.
CONCLUSIONS: Neoadjuvant enzalutamide and ADT was associated with favorable long-term oncologic outcomes, supporting continued investigation in localized PCa.

Keywords:  androgen receptor signaling inhibitors (ARSIs); cancer‐specific survival (CSS); neoadjuvant therapy; prostate cancer; robot‐assisted radical prostatectomy (RARP)

DOI:  https://doi.org/10.1002/pros.70093
Nat Commun. 2025 Nov 19. 16(1): 10160

Spatial multi-omics identifies aggressive prostate cancer signatures highlighting pro-inflammatory chemokine activity in the tumor microenvironment.

Sebastian Krossa, Maria K Andersen, Elise M Sandholm, Maximilian Wess, Antti Kiviaho, Abhibhav Sharma, Sini Hakkola, Yangyang Hao, Mohammed Alshalalfa, Elai Davicioni, Trond Viset, Øystein Størkersen, R Jeffrey Karnes, Daniel E Spratt, Guro F Giskeødegård, Matti Nykter, Morten B Rye, Alfonso Urbanucci, May-Britt Tessem.

Understanding the characteristics of the tumor microenvironment (TME) associated with aggressive prostate cancer (PCa) is essential for accurate diagnosis and treatment. We interrogated spatially resolved multi-omics data to find molecular stratifiers of aggressive PCa. We report an aggressive prostate cancer (APC) gene expression signature predictive of increased risk of relapse and metastasis in a cohort of 1,588 patients. Further, we present a chemokine-enriched-gland (CEG) signature specific to non-cancerous prostatic glands from patients with aggressive cancer. The CEG signature is characterized by upregulated expression of pro-inflammatory chemokines, club-like cell enrichment, and immune cell infiltration of surrounding stroma. The activity of both signatures is correlated with reduced citrate and zinc levels and loss of normal prostate secretory gland functions. In summary we report that an increased inflammatory status linked to chemokine production, club-like cell enrichment, and metabolic changes in normal-appearing prostatic glands is associated with the subsequent development of aggressive PCa.

DOI: https://doi.org/10.1038/s41467-025-65161-9
Cureus. 2025 Oct;17(10): e94872

Testosterone Replacement in Prostate Carcinoma: A Systematic Review of an Emerging Paradigm and Therapeutic Potential.

Jared Robinson, Indrajit Banerjee, Indraneel Banerjee.

  Prostate carcinoma is one of the most prevalent cancers among men. It is a dreaded outcome in the elderly male population and most commonly affects those 65 years of age and older. The etiologic nature of this common urological cancer is multifactorial and has an environmental, racial, and genetic interplay. One of the important factors believed to be involved in the causation of prostate carcinoma are androgens and prostatic sensitivity. Conventional treatment for this neoplasm ranges from radical surgery (prostatectomy), external beam radiation, brachytherapy, and androgen deprivation therapy (ADT) to radiopharmaceutical techniques. The conventional consensus is that external testosterone replacement therapy (TRT) is contraindicated in patients with prostate carcinoma or who are at risk thereof. The latest data and studies are challenging this notion and relationship. It is paramount that these misconceptions and older conventions are definitively and clearly corrected so as to ensure the best and most suitable treatment is made available to patients. This systematic review aims to find the relation between testosterone replacement therapy and prostate carcinoma. An extensive review of literature was done on the following databases: Google Scholar, Trip Database, EMBASE, PubMed, and PubMed Central to collate the latest data available on testosterone replacement therapy and prostate carcinoma for a systematic review. A combination of keywords was used for data extraction: "Hormone Replacement Therapy" OR "Prostate" OR "Prostatic Neoplasms" OR "Testosterone" OR "Urology." A triad of findings were noted: (1) exogenous testosterone replacement therapy is not contraindicated in men who have undergone definite treatment for their prostatic carcinoma (prostatectomy, external beam radiation, and/or chemotherapy), (2) exogenous testosterone replacement therapy does not alter intraprostatic dehydroepiandrosterone (DHEA) levels and thus does not attenuate or catalyze any change in the prostatic milieu, and (3) castration-resistant prostatic carcinoma does not undergo disease progression when treated using high-dose testosterone replacement therapy. No correlation between testosterone replacement therapy and prostate carcinoma exists, and TRT is not contraindicated in men post-definitive treatment for their primary neoplastic prostatic lesion. TRT is indicated in hypogonadal men post-primary treatment for its myriad of benefits and ultimate improvement of quality of life. The role of TRT in men prior to the diagnosis of prostatic carcinoma is unclear; thus, patients should give their informed consent before receiving the testosterone therapy. The role of TRT in prostate cancer is evolving, even in cases of advanced prostate cancer. One area of interest is bipolar androgen therapy (BAT), which has been studied in various clinical trials focused on castrate-resistant prostate cancer. Prostate cancer cells adapt to chronic low testosterone levels by increasing androgen receptor activity, resulting in a 30- to 90-fold rise in androgen receptor levels. Although this significant upregulation of androgen receptors can lead to castration resistance, it also creates a therapeutic vulnerability to treatment with high doses of testosterone, which can result in growth arrest or cell death. The term "bipolar" in BAT refers to the rapid switching between two extremes: from high testosterone levels (supraphysiologic) to near-castrate serum testosterone levels.

Keywords:  exogenous testosterone use; hormone replacement therapy; onco-urology; prostate; prostatic neoplasms; testosterone (tt)

DOI:  https://doi.org/10.7759/cureus.94872