bims-meproc 2026-03-08 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–03–08
twenty-one papers selected by
Grigor Varuzhanyan, UCLA

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.
Therapeutic interference of SREBP-mediated lipid metabolism by E-Xanthohumol attenuates prostate cancer progression.
Integrated scRNA-seq and bulk transcriptomics identify an amino acid metabolism-associated prognostic signature and highlight FUS as a potential driver in prostate cancer progression.
SCGB1A1 suppresses prostate cancer proliferation and metastasis by modulating the MAPK signaling pathway.
A Hierarchy of Luminal Transcription Factors Defines AR Cistrome and Is Lost in Neuroendocrine Prostate Cancer.
Zhoushi Qiling decoction inhibits neuregulin 1 secreted from cancer-associated fibroblasts to ameliorate enzalutamide resistance in prostate cancer.
PVT1 lincRNA signals an androgen-dependent transcriptional activation program of oncogenes in prostate cancer cells.
Clinical Utility of Transcriptomic Signatures to Identify Androgen Receptor and Neuroendocrine Signaling in Prostate Cancer.
lnc-ALX1-2:10 is a novel regulator that enhances proliferation, migration and invasion in prostate cancer cells.
Integrative multi-omics analysis reveals metabolic dysfunction signatures as critical determinants of prostate cancer prognosis and immunosuppressive microenvironments.
Serendipity, steroids and science.
GNL3 Orchestrates AR Transcriptional Programs to Drive Castration-Resistant Prostate Cancer and Immune Evasion.
A2AR as a key target for immune microenvironment remodeling in prostate cancer.
A phase I study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): dose escalation results.
Inhibition of c-FLIP alongside TRAIL treatment suppresses prostate cancer stem cell activity.
Prosta-omics: machine learning-driven TPSA prediction and molecular modeling of ASPM-inhibitors for prostate cancer treatment.
METTL3 promotes prostate cancer cell metastasis and EMT by mediating NUP210 m6A modification.
Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression.
Integrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression.
Dysregulation of ferroptosis-related genes and the ACSL4-mediated ferroptosis-PD-L1 axis in prostate cancer pathogenesis.
Differential regulation of EMT-related pathways by inflammatory microenvironment in 3D prostate spheroids and tumor-stroma interaction models.

Cancer Res. 2026 Mar 02. 86(5): 1095-1097

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Mohammadreza Alizadeh-Ghodsi, Andrew S Goldstein.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4807
Biochem Pharmacol. 2026 Mar 02. pii: S0006-2952(26)00191-7. [Epub ahead of print]248 117859

Therapeutic interference of SREBP-mediated lipid metabolism by E-Xanthohumol attenuates prostate cancer progression.

Jonathan Viehoever, Naveen Surya Velmani, Vignesh Basavaraj, Lahiru Gamage, Kai-Cheng Chan, Praveenkumar Basavaraj, Wen-Chin Huang.

  Aberrant lipid metabolism, driven by two key transcriptional regulators (SREBP-1 and SREBP-2) and their downstream enzymes, contributes to prostate cancer (PCa) development and progression to lethal castration-resistant PCa (CRPC). Targeting the SREBP-1 and SREBP-2 networks offer a promising therapeutic strategy by simultaneous inhibition of the multiple lipogenic pathways and the androgen receptor (AR). A naturally occurring prenylated chalcone, (E)-Xanthohumol (EXN), has emerged as a potent modulator of cellular metabolism, exhibiting the antioxidant properties and neuroprotective effects. However, the mechanistic impact of EXN on the dysregulated lipogenic pathways in PCa cells remains unknown. In this study, we aimed at revealing the molecular basis and determining the efficacy of EXN on PCa aggressiveness in vitro and in vivo. EXN significantly suppressed growth, migration and invasion in both androgen-dependent and CRPC PCa cells. Furthermore, EXN induced intrinsic caspase-dependent apoptosis in PCa cells. Remarkably, EXN downregulated expression of SREBP-1, SREBP-2 and their downstream regulated genes, including Fatty Acid Synthase (FASN) and β-Hydroxy β-methylglutaryl-CoA reductase (HMGCR), as well as AR. Lipidomic analysis demonstrated a significant decrease of triglycerides and cholesterol esters following EXN treatment in PCa cells. These overall effects were translated into attenuation of CRPC tumor growth in nude mice. In summary, our findings highlight EXN is a novel and potential anti-PCa agent via targeting dysregulated lipid metabolism mediated by SREBP. EXN would be able to overcome the shortcomings of current hormonal therapy against PCa emphasizing its clinical relevance.

Keywords:  (E)-Xanthohumol; Lipid metabolism; Lipidomics; Prostate cancer therapy

DOI:  https://doi.org/10.1016/j.bcp.2026.117859
Funct Integr Genomics. 2026 Mar 02. pii: 55. [Epub ahead of print]26(1):

Integrated scRNA-seq and bulk transcriptomics identify an amino acid metabolism-associated prognostic signature and highlight FUS as a potential driver in prostate cancer progression.

Jiangbei Yuan, Dawei Shen, Zixiang Pan, Fei Lv, Yue Zhao, Wei Zheng, Qiaoqiao Yin, LanJie Wu, Jianli Yu, Cheng'an Xu, Qiang He, Hongying Pan.

  Prostate cancer (PCa) exhibits marked metabolic heterogeneity, yet the prognostic implications of amino acid metabolism remain insufficiently characterized. In this study, we developed a 9-gene amino acid metabolic risk signature through an integrative analysis of single-cell and bulk transcriptomic datasets, leveraging machine learning to stratify patients into distinct prognostic subgroups. The model demonstrated robust predictive accuracy in both TCGA and independent GEO cohorts, with significant associations to immune microenvironment remodeling and therapeutic vulnerabilities. Mechanistically, multi-omics analyses (SCENIC, CellChat, pseudotime trajectory) delineated regulatory networks underlying amino acid metabolic dysregulation, highlighting FUS as a potential oncogenic regulator. Experimental validation across cellular, murine, and human models supported a role for FUS in promoting tumor aggressiveness. Through bioinformatic analysis, we identified potential signaling pathways underlying FUS involvement in prostate cancer progression. Our study establishes a clinically actionable amino acid metabolic signature and nomogram for PCa risk stratification, while suggesting FUS as a candidate therapeutic target. These findings bridge computational discovery with mechanistic validation, providing novel insights into the amino acid metabolic dependencies that govern prostate cancer (PCa) progression.

Keywords:  FUS; Machine learning; Prognostic model; Prostate cancer; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10142-026-01824-0
Int Urol Nephrol. 2026 Mar 04.

SCGB1A1 suppresses prostate cancer proliferation and metastasis by modulating the MAPK signaling pathway.

Wanli Zhao, Xudong Zhou, Guisong Qi, Yanan Zhou, Fan Li.

   BACKGROUND: Prostate cancer represents a prevalent urological malignancy, but the molecular mechanisms underlying the differentiation of distinct tumor cell subtypes have not been fully elucidated.
METHODS: We conducted an analysis of paired single-cell RNA sequencing data from the public database on prostate cancer, and discovered differentially expressed genes between tumor cells and normal epithelial cells. We evaluated the expression of SCGB1A1 in prostate cell lines and tissue samples, and assessed migration, invasion, and proliferation through CCK-8, EdU, wound healing, and Transwell experiments. We performed pathway enrichment analysis to explore the downstream mechanism of SCGB1A1 (Secretoglobin Family 1A Member 1).
RESULTS: Single-cell transcriptomic analysis revealed a marked reduction in SCGB1A1⁺ epithelial cells within tumor tissues, accompanied by an increased abundance of KLK3⁺ tumor epithelial cells. SCGB1A1 expression was significantly downregulated in both prostate cancer cell lines and tumor epithelial cells. Functional assays demonstrated that SCGB1A1 overexpression suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of prostate cancer cells. SCGB1A1 expression is negatively correlated with the activation of the MAPK signaling pathway, which may be associated with its tumor-suppressive effects.
CONCLUSION: Our findings identify SCGB1A1 as a previously underappreciated tumor-suppressive role in prostate cancer and reveal its role in modulating MAPK signaling and EMT. The depletion of SCGB1A1⁺ epithelial cells characterizes the malignant epithelial phenotype, suggesting its potential as a candidate diagnostic biomarker and therapeutic target that requires further clinical validation.

Keywords:  MAPK; Prostate cancer; SCGB1A1; Tumor metastasis and proliferation

DOI:  https://doi.org/10.1007/s11255-026-05076-6
Cancer Heterog Plast. 2025 ;pii: 0008. [Epub ahead of print]2(2):

A Hierarchy of Luminal Transcription Factors Defines AR Cistrome and Is Lost in Neuroendocrine Prostate Cancer.

Viriya Keo, Xiaodong Lu, Lourdes Brea, Xianglin Shi, Jindan Yu, Jonathan C Zhao.

  Androgen receptor (AR) is a hormonal transcription factor (TF) that binds to cis-regulatory elements of prostate lineage-specific genes to govern androgen response and progression of prostate cancer (PCa). This AR cistrome has been reported to be controlled by multiple chromatin-pioneering factors such as FOXA1, HOXB13, and GATA2. However, how these pioneer factors cooperate to regulate the AR cistrome remains unclear. Here, through comparative ChIP-seq analyses, we found that FOXA1 alone was sufficient to recruit AR to its binding sites regardless of H3K4me1. FOXA1 further enlisted HOXB13 and/or GATA2 to augment AR binding and enhancer activation, while HOXB13 and/or GATA2 alone were unable to recruit each other, nor AR. Moreover, HOXB13 knockdown attenuated AR and GATA2 expression and chromatin binding but failed to reprogram their cistromes, suggesting a role as a cofactor rather than a pioneer factor. During the neuroendocrine transformation (NET) of PCa, AR, GATA2, and HOXB13 were lost due to promoter hypermethylation, whereas FOXA1 was down-regulated by transcriptional repression. Lastly, through analyses of tissue microarrays, we confirmed that FOXA1 protein levels were drastically reduced in neuroendocrine PCa, as compared to AR-positive PCa. Therefore, our findings report a hierarchical network of TFs, pioneered by FOXA1 and facilitated by HOXB13 and GATA2, that defines lineage-specific AR cistrome and was lost during NET of PCa.

Keywords:  ChIP-seq, pioneer factor, cistrome reprogramming; FOXA1, GATA2, DNA methylation; HOXB13; Neuroendocrine prostate cancer

DOI:  https://doi.org/10.47248/chp2502020008
J Tradit Complement Med. 2026 Mar;16(2): 224-231

Zhoushi Qiling decoction inhibits neuregulin 1 secreted from cancer-associated fibroblasts to ameliorate enzalutamide resistance in prostate cancer.

Chunyu Wang, Hongwen Cao, Peng Sun, Lei Chen, Yigeng Feng, Renjie Gao.

   Background and aim: Zhoushi Qiling decoction (ZQD) has emerged as a promising therapeutic agent for improving outcomes in prostate cancer treatment. This study aimed to evaluate the efficacy of ZQD on enzalutamide-resistant prostate cancer cells and to elucidates the underlying mechanisms.
Experimental procedure: A co-culture model consisting of cancer-associated fibroblasts (CAFs) and enzalutamide-resistant prostate cancer cells was established and treated with ZQD-containing serum. Cell proliferation and viability were assessed using colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The anti-tumor effects of ZQD were further evaluated in an in vivo xenograft model using enzalutamide-resistant PC3-EnzR cells treated with ZQD for 28 days. Expression of relevant biomarkers in cell lines and tumor tissues was analyzed by qRT-PCR and Western blotting.
Results: ZQD-containing serum inhibited the expression of neuregulin 1 (NRG1) in CAFs. It also reversed CAF-induced enzalutamide resistance and reduced CAF-stimulated proliferation of enzalutamide-resistant prostate cancer cells. In addition, ZQD suppressed NRG1 secretion and phosphorylation of human epidermal growth factor receptor 3 (HER3) in these cells. The serum also demonstrated inhibitory effects on matrix metalloproteinases (MMP-1 and MMP-9) in enzalutamide-resistant prostate cancer cells. In vivo, ZQD significantly suppressed tumor growth and reduced NRG1 expression.
Conclusion: ZQD effectively inhibits NRG1 secretion from CAFs and mitigates enzalutamide resistance in prostate cancer. These findings provide a scientific basis for the potential clinical application of ZQD in overcoming enzalutamide resistance in prostate cancer treatment.

Keywords:  Cancer-associated fibroblasts; Enzalutamide resistance; NRG1; Prostate cancer; Zhoushi Qiling decoction

DOI:  https://doi.org/10.1016/j.jtcme.2025.07.002
Int J Cancer. 2026 Mar 06.

PVT1 lincRNA signals an androgen-dependent transcriptional activation program of oncogenes in prostate cancer cells.

Maria Gabriela Berzoti-Coelho, Fabio Nunes de Mello, Ana Carolina Tahira, Gabriel Nakanishi Fortes, Agatha Fischer-Carvalho, Pedro Jardim Poli, Murilo Sena Amaral, Sergio Verjovski-Almeida.

  Prostate cancer is the most prevalent malignancy among men and is driven by multiple factors, including androgen signaling and its receptor. Long non-coding RNAs, such as PVT1, play key roles in cancer, particularly by regulating gene expression. PVT1 is upregulated in several cancer types and has been shown to interact with the androgen receptor in prostate cells. This study investigates how PVT1 contributes to the prostate cancer phenotype under androgen stimulation. Knockdown of PVT1 was achieved using CRISPR-Cas13d in LNCaP prostate cancer cells subjected to androgen (R1881) or vehicle treatment. Cellular proliferation, invasion, and apoptosis rates were assessed, alongside RNA sequencing (RNA-seq) to analyze genome-wide transcriptomic changes. Six epigenetic marks-AR, EZH2, H3K4me1, H3K4me3, H3K27me3, and H3K27ac-were examined using CUT&RUN. PVT1 knockdown led to a significant reduction in cell proliferation and an increase in apoptosis signaling. Oncogenes such as MYC, AKT1, AKT2, cyclins CCNA2, CCNB1, CCNB2, CCNE1, CCNE2 and cyclin-dependent kinases CDK1 and CDK4, which were upregulated under androgen treatment, exhibited a significantly reduced expression following PVT1 knockdown, thereby modulating cancer-associated oncogenic pathways. Epigenetically, PVT1 knockdown markedly decreased the occupancy of transcriptionally activating epigenetic marks-H3K4me1, H3K4me3, and H3K27ac-on oncogenes, regardless of androgen presence. Analysis of enriched transcription factors associated with the altered genes revealed a regulatory network linked to prostate cancer pathogenesis. PVT1 drives a genome-wide epigenetic reprogramming in prostate cells, underscoring the role of PVT1 as a positive regulator of oncogenic pathways in prostate cancer and highlighting PVT1's potential as a therapeutic target.

Keywords:  PVT1; androgen receptor signaling; epigenetic regulation; long non‐coding RNA; prostate cancer

DOI:  https://doi.org/10.1002/ijc.70417
JCO Precis Oncol. 2026 Mar;10 e2500756

Clinical Utility of Transcriptomic Signatures to Identify Androgen Receptor and Neuroendocrine Signaling in Prostate Cancer.

Yu-Wei Chen, Joanne Xiu, Kelsey Anne Poorman, Charles J Ryan, Brady Gilg, Matthew James Oberley, Gloria Sura, George W Sledge, Shuang G Zhao, Alan Tan, Himisha Beltran, Rana R McKay.

PURPOSE: This study aimed to define molecular subtypes of prostate cancer by integrating androgen receptor (AR) signaling, neuroendocrine prostate cancer (NEPC) transcriptional signatures, and genomic alterations to inform biomarker-driven therapies in metastatic castration-resistant prostate cancer.
METHODS: We analyzed 8,019 prostate tumors using DNA/RNA sequencing (Caris Life Sciences), classifying them into four molecular subtypes (AR+/NE-, AR-/NE+, AR+/NE+, AR-/NE-). Genomic alterations, cell surface target expression, and overall survival (OS) were evaluated.
RESULTS: Of the 8,019 tumors, 87.2% were adenocarcinoma, 1.9% NEPC, and 0.4% had mixed histology; 63% were from primary sites and 36.5% from metastases. The median age was 68 years; 63% were White, 15% Black, and 2.6% Asian or Pacific Islander. Most tumors were classified as AR+/NE- (91%), and 4.6% were AR-/NE+. TP53 and PTEN alterations were enriched in AR-negative subtypes, whereas SPOP mutations were more frequent in AR+ tumors. FOLH1 (prostate-specific membrane antigen) expression was the highest in AR+ tumors, whereas DLL3 expression was elevated in NE+ tumors. Median OS was significantly longer in tumors with high AR signaling (55.0 v 14.0 months, P < .00001) and lower with the NEPC signature (54.3 v 16.1 months, P < .00001). Combined stratification showed the most favorable outcome in AR+/NE- tumors (55.3 months) and the poorest in AR-/NE+ tumors (12.0 months).
CONCLUSION: Prostate cancer exhibits distinct molecular subtypes defined by AR signaling activity, NEPC transcriptional profiles, and genomic alterations. These biologically and clinically relevant subgroups provide a framework for precision oncology approaches and inform patient selection for biomarker-driven trials such as the ongoing PREDICT study (ClinicalTrials.gov identifier: NCT06632977).

DOI: https://doi.org/10.1200/PO-25-00756
Sci Rep. 2026 Mar 03.

lnc-ALX1-2:10 is a novel regulator that enhances proliferation, migration and invasion in prostate cancer cells.

Xinjun Wang, Qian Zong, Yue Bu, Bin Zhou, Xuqiang Wang, Zhangqun Li, Guangcheng Luo.

  Although long noncoding RNAs (lncRNAs) have been implicated in the progression of prostate cancer (PCa), the functional roles of many of these molecules, especially in metastasis, remain poorly understood. To identify novel lncRNAs linked to PCa malignant phenotypes, we analyzed the differences in lncRNA expression between the highly metastatic PCa cell line (PC-3 M-1E8) and the poorly metastatic PCa cell line (PC-3 M-2B4) using transcriptome sequencing. This differential expression was confirmed by RT-qPCR, which showed that the lnc-ALX1-2 gene cluster (including lnc-ALX1-2:5, lnc-ALX1-2:7, lnc-ALX1-2:10) was significantly upregulated in PC-3 M-1E8 cells. Functional studies demonstrated that knockdown of the lnc-ALX1-2 gene cluster suppressed proliferation, migration, and invasion in PC-3 M-1E8 cells, with lnc-ALX1-2:10 showing the most prominent effect. Transcriptome analysis further revealed that lnc-ALX1-2:10 knockdown altered the expression of 194 genes related to both proliferation and migration. RT-qPCR and Western blot validated that lnc-ALX1-2:10 knockdown downregulated pro-tumorigenic factors (CCNE1, PDGFRA, ANGPT4) and EMT markers (N-cadherin, Snail, Vimentin), while upregulating ITGAL and E-cadherin. In vivo, lnc-ALX1-2:10 knockdown obviously decreased tumor volume but had no effect on mouse body weight, and molecular analysis of xenograft tumors confirmed consistent expression changes of key proteins as in vitro. Collectively, our findings identify lnc-ALX1-2:10 as a novel lncRNA that promotes aggressive phenotypes in PCa, highlighting its potential as a therapeutic target for metastatic disease.

Keywords:  Lnc-ALX1-2:10; Migration; Proliferation; Prostate cancer; Transcriptome sequencing

DOI:  https://doi.org/10.1038/s41598-026-42299-0
Eur J Med Res. 2026 Mar 03.

Integrative multi-omics analysis reveals metabolic dysfunction signatures as critical determinants of prostate cancer prognosis and immunosuppressive microenvironments.

Xiangqian Nie, Zhenlin He, Kun Wang, Decai Zhu, Wei Li, Lei Zhang, Ying Yu.

   BACKGROUND: Metabolic reprogramming is a hallmark of cancer. However, the precise mechanisms by which specific metabolic pathways drive prostate cancer (PCa) progression and shape the tumor microenvironment remain poorly defined.
METHODS: A machine learning-derived Metabolic Dysfunction Signature (MODS) was developed and validated as a prognostic model. Its clinical relevance was established through multidimensional assessment, demonstrating significant associations with: (1) adverse clinical outcomes, (2) genomic instability, and (3) distinct therapeutic response profiles. Pathway enrichment and transcriptomic deconvolution (via CIBERSORT and ssGSEA) of TCGA and GEO cohorts were performed to characterize MODS-associated remodeling of the tumor microenvironment. Single-cell resolution analysis, utilizing the AUCell algorithm and CellChat ligand-receptor networking, was conducted to elucidate MODS-mediated epithelial-immune crosstalk, highlighting its role in establishing an immunosuppressive niche. Validation of HPRT1 expression and function using human protein atlas database and in vitro models. Furthermore, molecular docking simulations were employed to evaluate the potential targeting of HPRT1 by prevalent environmental compounds.
RESULTS: The MODS prognostic model demonstrated robust predictive performance across three independent validation cohorts. MODS scores were positively correlated with adverse patient outcomes and advanced clinical stage. Notably, high-MODS tumors exhibited significantly greater genomic instability, reflected in a higher tumor mutational burden, and heightened resistance to conventional pharmacotherapies. Enrichment analysis revealed significant activation of proliferative signaling and oncogenic metabolic pathways in high-MODS tumors. Conversely, immune infiltration analysis indicated that high-MODS tumors were characterized by enhanced immunosuppressive features, including increased M2 macrophage infiltration. Single-cell analysis established that metabolically dysregulated epithelial cells, as defined by high MODS activity, functioned as central drivers of both poor prognosis and immunosuppressive microenvironment formation. Functional assays confirmed the oncogenic properties of HPRT1, promoting PCa cell proliferation and migration. Molecular docking simulations identified HPRT1 as a convergent molecular target for multiple environmental carcinogens implicated in PCa initiation.
CONCLUSION: This study defines a prevalent metabolic dysfunction signature in PCa that is integrally linked to patient prognosis, genomic instability, therapeutic resistance, and the establishment of an immunosuppressive tumor microenvironment. Furthermore, HPRT1 is functionally validated as a promoter of PCa progression and is positioned as a novel potential biomarker and therapeutic target for both intervention and prognosis assessment.

Keywords:  HRPT1; Metabolic disorders; Prostate cancer; Single cell sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40001-026-04049-w
J Steroid Biochem Mol Biol. 2026 Feb 26. pii: S0960-0760(26)00038-5. [Epub ahead of print] 106972

Serendipity, steroids and science.

Nima Sharifi.

  The androgen signaling pathway is probably the most important pathway in enabling prostate cancer progression but it also plays essential roles in numerous processes in normal physiology. Both testosterone and dihydrotestosterone are potent androgens that activate the androgen receptor (AR). The essentiality of the androgen pathway in prostate cancer is evidenced in part by the reactivation of AR in prostate cancer that becomes resistant to treatment by gonadal testosterone deprivation. Furthermore, steroid metabolic processes that allow the regeneration of potent androgens in prostate cancer tissues drive this treatment-resistant state, as is made clear by the survival benefit of blocking the synthesis of non-gonadal androgens, e.g., with abiraterone. Here, I narrate and review the process that led to a series of discoveries in androgen metabolism from our group. In this perspective and mechanistic narrative review, I give an honest description of the accidental nature of some of our initial findings, followed by data-driven hypothesis refinement and subsequent studies that illuminate elements of androgen metabolism, with a focus on metabolism of carbon 3, carbon 5 and carbon 17 of the steroid backbone.

Keywords:  androgens; enzymes; metabolism; prostate cancer; steroids

DOI:  https://doi.org/10.1016/j.jsbmb.2026.106972
Adv Sci (Weinh). 2026 Mar 02. e16411

GNL3 Orchestrates AR Transcriptional Programs to Drive Castration-Resistant Prostate Cancer and Immune Evasion.

Cuiting Zhang, Tin Long Cheong, Nitin Narwade, Dandan Dong, Mokan Deng, Zhengqiang Miao, Zhaoqiang Ding, Wenchao Li, Kate Man Kei Lei, Gong-Hong Wei, Terence Chuen Wai Poon, Chu-Xia Deng, Edwin Cheung.

  Androgen receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate cancer (CRPC), yet the mechanism remains incompletely understood. Through proteomic profiling of CRPC and primary PCa cells, we identify G Protein Nucleolar 3 (GNL3) as a novel AR coregulator. GNL3 physically interacts with AR, enhances its chromatin occupancy, and directly coactivates transcriptional programs that promote cell proliferation, including NEK2 and CDC20. Concurrently, GNL3 functions as a corepressor of immune-responsive genes such as CXCL10 and TAP1 via class I histone deacetylases (HDACs), thereby facilitating CD8+ T cell elimination and establishing an immunosuppressive tumor microenvironment. GNL3 expression and AR-GNL3 complex formation progressively increase from normal prostate to CRPC and correlate with poor clinical outcomes. Functionally, GNL3 knockdown sensitizes CRPC cells to AR antagonists and impairs tumor growth and metastasis. Furthermore, we demonstrate that combinatorial inhibition of NEK2, class I HDACs, and AR signaling can be a potential therapeutic strategy for CRPC. Overall, these findings establish GNL3 as a dual-function AR coregulator and therapeutic target, providing mechanistic insights into transcriptional regulation and immune evasion in advanced PCa.

Keywords:  AR coregulator; GNL3; castration‐resistant prostate cancer; immunosuppression

DOI:  https://doi.org/10.1002/advs.202516411
Transl Oncol. 2026 Feb 27. pii: S1936-5233(26)00057-4. [Epub ahead of print]66 102720

A2AR as a key target for immune microenvironment remodeling in prostate cancer.

Lanzhi Yan, Ze Yang, Xiaojing Zhao, Yong Chen, Zhe Wang.

  This study elucidates the critical role of adenosine A2A receptor (A2AR) signaling in prostate cancer progression through comprehensive molecular characterization and clinical validation, demonstrating that A2AR overexpression in prostate cancer cells drives profound immunosuppression via coordinated upregulation of CD73-mediated adenosine production, subsequent activation of immunosuppressive pathways including ARG1, TGF-β, and IL-10 secretion, and induction of immune checkpoint molecules PD-L1 and Galectin-9, which collectively promote myeloid-derived suppressor cell expansion and CD8+ T cell exhaustion while creating an immunologically privileged tumor microenvironment. Clinical correlation analyses across multiple patient cohorts reveal that elevated A2AR expression serves as a powerful independent predictor of aggressive disease progression and poor clinical outcomes, particularly in metastatic castration-resistant prostate cancer, where it exhibits stronger prognostic value than in other solid tumors. A2AR activation not only helps tumors resist immune checkpoint inhibitors but also blocking A2AR can work well with PD-1/PD-L1 treatments by reversing the immune suppression caused by adenosine and boosting the body's ability to fight tumors. The potential for using these findings in real-world clinical settings is backed by models showing that combining A2AR expression with adenosine pathway activity and immune profiling greatly improves the accuracy of risk assessment compared to standard prognostic markers, while earlier studies show that targeting this pathway could be a viable treatment option. These results collectively position A2AR as a master regulator of prostate cancer immunosuppression and a promising biomarker-guided therapeutic target, particularly for combination immunotherapy approaches in advanced disease settings where current treatment options remain limited.

Keywords:  A2AR; Immunotherapy; Metastatic castration-resistant prostate cancer; Prostate cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2026.102720
Cancer Res Commun. 2026 Mar 05.

A phase I study of hydroxychloroquine and suba-itraconazole in men with biochemical relapse of prostate cancer (HITMAN-PC): dose escalation results.

Barak Talmor, Stefano Marastoni, Brandon Lau, Andrew O Yam, Nicole Yeung, Hui-Ming Lin, Zhu Juan Li, Henry Woo, Ganes Pranavan, Phillip D Stricker, Lisa G Horvath, Marianne Koritzinsky, Bradly G Wouters, Megan Crumbaker, Anthony M Joshua.

PURPOSE: Biochemical recurrence (BCR) of prostate cancer (PCa) presents a clinical challenge with limited systemic treatment options beyond androgen deprivation therapy (ADT), which carries significant morbidity. Preclinical data suggest lysosomal homeostasis, including cholesterol trafficking and pH regulation, is a therapeutic vulnerability in hormone-dependent cancers. We therefore conducted HITMAN-PC, a phase I trial evaluating Suba-Itraconazole (SI) and hydroxychloroquine (HCQ) in men with BCR Patients and Methods:The synergy of SI and HCQ was validated in hormone-sensitive and castration-resistant prostate cancer cell lines. The HITMAN-PC trial then used a rolling-six design to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of HCQ with a fixed SI dose (150 mg twice daily). Secondary endpoints included safety, PSA kinetics (PSA-PFS, time to ADT), and exploratory pharmacokinetic and lipidomic profiling.
RESULTS: Itraconazole showed dose-dependent cytotoxicity, with synergy in LNCaP-derived hormone-sensitive and resistant lines. Eleven patients were enrolled. Two dose-limiting toxicities at HCQ 600 mg twice daily (grade 3 diarrhea and ALT elevation) defined this level as the MTD with SI 150 mg twice daily. Common adverse events were hypertension, QTc prolongation, diarrhea, and nausea; no grade 4 events occurred. No PSA declines ≥50% were observed, though most patients achieved PSA stabilization. Median PSA-PFS, time to ADT, and metastasis-free survival were 5.5, 14.3, and 15.9 months, respectively. Lipidomic profiling revealed 240 treatment-associated lipid changes, with sphingomyelin and triacylglycerol species correlating with PSA-PFS.
CONCLUSIONS: Despite limited clinical activity overall, the identified lipidomic signatures provide proof-of-concept for using plasma lipidomics to monitor pharmacodynamic activity in future metabolism-targeted trials.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0010
Br J Cancer. 2026 Mar 03.

Inhibition of c-FLIP alongside TRAIL treatment suppresses prostate cancer stem cell activity.

Daniel J Turnham, Rhiannon French, Fiona M Frame, Valerie S Meniel, Norman J Maitland, Richard W E Clarkson.

BACKGROUND: Prostate cancer is a leading cause of cancer-associated death in men worldwide. Inhibition of the Cellular FLICE-like Inhibitory Protein (cFLIP), which is overexpressed in prostate cancer, alongside TRAIL treatment can trigger apoptosis and suppress cancer stem cell (CSC) activity in different cancer types but has not been fully explored in prostate cancer.
METHODS: Established and primary prostate cancer lines were treated with the cFLIP inhibitor, OH14, in combination with recombinant TRAIL to investigate changes in viability and colony forming potential. Patient-derived xenograft (PDX) tumour cells were treated ex vivo and re-transplanted into mice in limiting dilution assays. Docetaxel resistant PC-3 cells were also treated with OH14 +/- docetaxel, while PDX tumours were treated in vivo with this combination.
RESULTS: Combined OH14 and TRAIL treatment induced a potent apoptotic response in prostate cancer cells, significantly reducing viability and CSC activity compared to single agents. OH14 also sensitised tumour cells to docetaxel both in vitro and in vivo.
CONCLUSIONS: Inhibition of cFLIP in combination with either TRAIL or docetaxel has the potential to be used as a novel therapeutic approach to provide more potent, long-lasting benefits to men with prostate cancer.

DOI: https://doi.org/10.1038/s41416-026-03359-4
Mol Divers. 2026 Mar 04.

Prosta-omics: machine learning-driven TPSA prediction and molecular modeling of ASPM-inhibitors for prostate cancer treatment.

Kashif Iqbal Sahibzada, Shumaila Shahid, Saba Shahid, Andleeb Batool, Yuansen Hu, Dong-Qing Wei.

  Prostate cancer exhibits complex transcriptional heterogeneity that underlies disease progression and therapeutic resistance. We developed an integrative omics-to-therapy pipeline to identify actionable biomarkers and screen drug candidates using a combination of single-cell transcriptomics, cheminformatics, and machine learning. Single-cell RNA sequencing (scRNA-seq) of prostate cancer tissues enabled fine-grained clustering and differential gene expression analysis across malignant and non-malignant cell populations. ASPM (Abnormal Spindle Microtubule Assembly) emerged as a statistically significant and cell-type-enriched biomarker associated with proliferative tumor phenotypes. We curated a library of drug-like molecules and developed Prosta-Omics, a supervised machine learning tool trained to predict Topological Polar Surface Area (TPSA) from molecular SMILES using a Random Forest model. High-ranking compounds as predicted by Prosta-Omics were docked against a 3D model of ASPM revealing multiple candidates with strong binding affinities and key interaction motifs. The drugs with higher docking score were subjected into molecular dynamics (MD) simulation and ADMET analysis. This integrative strategy highlights ASPM as a viable therapeutic target and introduces Prosta-Omics as a robust predictive platform bridging single-cell analytics with AI-driven drug discovery for precision oncology in prostate cancer.

Keywords:  ASPM; MD simulation; Machine TPSA; Prostate cancer; scRNA-seq

DOI:  https://doi.org/10.1007/s11030-026-11470-0
Mutat Res. 2026 Feb 23. pii: S1386-1964(26)00003-5. [Epub ahead of print]832 111930

METTL3 promotes prostate cancer cell metastasis and EMT by mediating NUP210 m6A modification.

Shaoxing Wang, Jinming Li, Jun Jiang, Jiahao Liu, Shusen Zuo.

   BACKGROUND: Prostate cancer (PCa) is an age-related epithelial malignancy with high metastatic potential. Although nucleoporin 210 (NUP210) is implicated in tumor progression, its role and mechanism in PCa metastasis remain unexplored.
METHODS: Bioinformatics analysis (Gene Expression Omnibus (GEO)/The University of Alabama at Birmingham CANcer data analysis Portal (UALCAN) databases) and experimental validation (quantitative real-time PCR (qRT-PCR) and western blot) were applied to assess the expression of NUP210, methyltransferase-like 3 (METTL3), metastasis-related markers, and epithelial-mesenchymal transition (EMT)-related markers. Functional assays (transwell, in vivo metastasis models) and mechanistic studies (methylated RNA immunoprecipitation (MeRIP), RNA binding protein immunoprecipitation (RIP), and mRNA stability assays) were performed to elucidate the METTL3/NUP210 axis.
RESULTS: NUP210 and METTL3 were highly expressed in PCa tissues and cells. Knockdown of NUP210 significantly inhibited PCa metastasis and EMT. Also, the animal study revealed that NUP210 silencing could inhibit the lung metastasis of PCa in vivo. METTL3-mediated N6-methyladenosine (m6A) modification stabilized NUP210 mRNA, and rescue experiments confirmed that NUP210 overexpression reversed the inhibitory effects of METTL3 silencing on PCa cell metastasis and EMT.
CONCLUSION: The METTL3-mediated m6A modification of NUP210 may promote PCa metastasis and EMT. This newly identified METTL3/NUP210 axis deepens the understanding of PCa progression and suggests its potential for further therapeutic exploration.

Keywords:  Methyltransferase-like 3; N6-methyladenosine; Nucleoporin 210; Prostate cancer

DOI:  https://doi.org/10.1016/j.mrfmmm.2026.111930
Cancer Res. 2026 Mar 05.

Intercepting YAP Activation in Prostate Cancer Blocks Neuroendocrine Progression.

Arianna Brevi, Marco Lorenzoni, Sara Caputo, Yasutaka Yamada, Matteo Grioni, Laura L Cogrossi, Laura Martinez-Vidal, Valeria Cassina, Deborah Cipria, Chiara Venegoni, Paola Zordan, Vittoria Matafora, Anna S Tascini, Nazario P Tenace, Riccardo Campanile, Vito Cucchiara, Valeria Pinna, Elena Jachetti, Rossella Galli, Angela Bachi, Maurizio Colecchia, Alberto Briganti, Massimo Freschi, Francesco Mantegazza, Angelo Lombardo, Francesca Demichelis, Himisha Beltran, Massimo Alfano, Matteo Bellone.

The emergence of the neuroendocrine phenotype in castration resistant prostate cancer (CRPC) is associated with poor patient prognosis. Castration-induced death of fully differentiated, androgen-sensitive PC cells might foster interactions among rare androgen-independent, poorly differentiated cancer cells and the extracellular matrix (ECM) that promotes the development of neuroendocrine PC (NEPC). Here, we investigated physical and molecular interactions between poorly differentiated PC cells with exocrine (PAC) or neuroendocrine features (PNE), which recapitulated pre-existing human CRPC-like cells, and decellularized prostate ECM. Without androgens, PAC cells and PC-derived ECM promoted in vitro invasiveness of PNE cells by inducing integrin α2 upregulation and YAP activation, indicating a cell-to-cell and cell-to-matrix contact-driven process. Inhibition of RANK/RANKL and NF-κB prevented integrin α2 upregulation in PNE cells, and integrin α2β1 and YAP inhibition also reduced PNE invasiveness. Microenvironment-conditioned PNE cells showed YAP-dependent metastatic behavior in vivo, and YAP inhibition suppressed the development of NEPC and metastasis in castration-naïve mice and of CRPC-NE in transgenic PC mice. Importantly, YAP inhibitors also restrained the growth of human CRPC organoids. These findings unveil mechanisms of NEPC development and implicate the integrin α2-YAP axis as a therapeutic target in PC patients receiving androgen-deprivation therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2704
Mol Cancer. 2026 Feb 28.

Integrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression.

Hongyuan Yu, Yusong Wang, Mingcong He, Yiming Chen, Jianbin Bi, Xuyong Lin, Xiaolu Cui.



Keywords:  Lineage plasticity; Prostate cancer; Single-cell RNA sequencing; Spatial transcriptomics; Treatment resistance; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02617-6
Cancer Cell Int. 2026 Mar 03.

Dysregulation of ferroptosis-related genes and the ACSL4-mediated ferroptosis-PD-L1 axis in prostate cancer pathogenesis.

Chao Yang, Hengbing Wang, Hao Meng, Fei Mao.



Keywords:  Ferroptosis; PD-L1; Prostate Cancer; ACSL4

DOI:  https://doi.org/10.1186/s12935-026-04249-8
Exp Cell Res. 2026 Feb 27. pii: S0014-4827(26)00079-0. [Epub ahead of print]457(2): 114962

Differential regulation of EMT-related pathways by inflammatory microenvironment in 3D prostate spheroids and tumor-stroma interaction models.

Fersu G A Calisir, Suleyman Arziman, Elif Isel, Bilge Debelec Butuner.

  Chronic inflammation plays a major role in the initiation, progression, and metastasis of prostate cancer (PCa) by driving tumorigenic processes such as Epithelial-Mesenchymal Transition (EMT). To investigate these mechanisms in physiologically relevant settings, we optimized two complementary in vitro tumor models: 3D prostate spheroids that mimics multicellular interactions and an epithelial-myofibroblast co-culture system that reflects key tumor-stroma dynamics under inflammatory conditions. Our optimization revealed that successful spheroid formation depends on cell line-specific molecular features rather than a universal spheroid size. Compared with conventional 2D cultures, inflammatory stimuli modulated EMT mediators significantly in a cell line-dependent manner; notably, fibronectin, vimentin, and TWIST1 were differentially regulated in 3D spheroids, indicating enhanced invasive features driven by inflammatory cues. The co-culture model successfully represented reactive stroma formation, and stromal influence dramatically shaped inflammation-induced anoikis resistance and cell migration. Overall, our findings demonstrated that tumor-stroma interactions critically contribute to the impact of inflammation on EMT in PCa. Our optimized 3D spheroid and co-culture models provide a robust and powerful platform to unravel the functional consequences of inflammation and offer mechanistic insight into cellular processes underlying PCa progression, supporting the development of targeted therapeutic strategies.

Keywords:  Epithelial-mesenchymal transition; Epithelial-myofibroblast co-culture; Inflammation-induced tumorigenesis; Prostate cancer spheroid; Tumor-stroma interaction

DOI:  https://doi.org/10.1016/j.yexcr.2026.114962