bims-meproc 2026-03-29 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–03–29
twenty papers selected by
Grigor Varuzhanyan, UCLA

Intermittent Fasting and Androgen Receptor Signaling in Prostate Cancer: Metabolic Crosstalk and Therapeutic Implications.
KDM7A and KDM1A inhibition suppresses tumour promoting pathways in prostate cancer.
Genistein-Butein Co-Treatment Suppresses Glycolytic Metabolism and Induces Apoptotic Signaling in PC-3 Prostate Cancer Cells.
A network pharmacology-guided multi-omics and spatial single-cell framework nominates WT1 as a spironolactone-linked immune biomarker in prostate cancer.
The Role of Gut Microbiome in Prostate Cancer: Current Evidence and Emerging Opportunities.
Phellinus linteus polysaccharides inhibit castration-resistant prostate cancer progression possibly via dual modulation of PIK3R1 and PGC-1α: a preclinical evaluation.
LAMC3 promotes the development of prostate cancer via modulating the cell cycle progression.
SMARCA4 promotes lineage plasticity and enzalutamide resistance in prostate cancer by regulating PROX1 via H3K27 acetylation.
Aryl hydrocarbon receptor is critical for both AR-dependent and AR-indifferent enzalutamide resistance in castration-resistant prostate cancer.
Probing uric acid-related prognostic genes and their molecular mechanisms in prostate cancer based on transcriptomic data.
Insulin-like growth factor binding protein-3 serves as a biomarker for resistance to enzalutamide in prostate cancer.
USP52 impedes malignant progression and cell stemness in prostate cancer by deubiquitinating RBM5 to down-regulate NCAPG2.
Paired-sample Analysis of ERG Expression and TMPRSS2-ERG Fusion in Treatment-induced Neuroendocrine Prostate Cancer.
Nanozyme-Mediated PROTACs Delivery for Targeted Protein Degradation and Ferroptosis Sensitization in Prostate Cancer.
Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage.
Quercetin Inhibits AKT Ser473 Phosphorylation and Disrupts AKT-Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Cells.
Hypoxia-Driven Mechanisms of Drug Resistance in Prostate Cancer.
Single-Cell and Spatial Transcriptomic Profiling Reveals Epithelial Functional States and Fibroblast Phenotypes in Hormone Therapy-Naïve Localized Prostate Cancer.
The hexosamine biosynthetic pathway alters the cytoskeleton to modulate cell proliferation and migration in aggressive prostate cancer.
Adaptation of MALDI-TOF MS Technique for Tracking Changes in the Urinary Microbiome During and After Radiotherapy for Prostate Cancer.

Int J Mol Sci. 2026 Mar 13. pii: 2652. [Epub ahead of print]27(6):

Intermittent Fasting and Androgen Receptor Signaling in Prostate Cancer: Metabolic Crosstalk and Therapeutic Implications.

Grażyna Gromadzka, Maria Bendykowska.

  Prostate cancer (PCa) progression is critically driven by androgen receptor (AR) signaling, which integrates hormonal cues with metabolic programs supporting tumor growth, survival, and therapy resistance. Emerging evidence suggests that intermittent fasting (IF) and related dietary interventions-such as time-restricted eating (TRE), alternate-day fasting (ADF), and fasting-mimicking diet (FMD)-modulate systemic metabolism, including reductions in insulin and insulin-like growth factor 1 (IGF-1), and induce intracellular nutrient stress that can influence AR activity, splice variant expression (e.g., AR-V7), and downstream metabolic pathways. This systematic literature review (Scopus, PubMed, Web of Science; publications up to December 2025; search terms: "prostate cancer," "androgen receptor," "AR splice variants," "intermittent fasting," "fasting mimicking diet", "metabolism," "therapy resistance") summarizes preclinical and clinical studies addressing the impact of IF on AR signaling, lipogenesis, mitochondrial function, redox homeostasis, and therapy response. Preclinical studies indicate that IF can reduce AR expression, impair nuclear translocation, modulate AR splice variants such as AR-V7 via nutrient-sensitive splicing mechanisms, and enhance sensitivity to androgen deprivation therapy and AR-targeted agents. Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer.

Keywords:  AMPK; AR-V7; androgen receptor; diet; fasting mimicking diet; intermittent fasting; lipogenesis; metabolism; prostate cancer; therapy resistance; time-restricted eating

DOI:  https://doi.org/10.3390/ijms27062652
Mol Oncol. 2026 Mar 23.

KDM7A and KDM1A inhibition suppresses tumour promoting pathways in prostate cancer.

Jennie N Jeyapalan, Veronika M Metzler, Simone de Brot, Corinne L Woodcock, Anna E Harris, Jennifer Lothion-Roy, Emeli M Nilsson, Atara Ntekim, Michael S Toss, Jenny L Persson, Francesca Khani, Brian D Robinson, Lorraine J Gudas, Emad Rakha, David M Heery, Catrin S Rutland, Nigel P Mongan.

  Treatment resistance has become a major challenge in cancer research, particularly for patients with advanced castration resistant prostate cancer (CRPC) where no curative therapies are available. Epigenetic alterations play a significant role in cancer progression. In prostate cancer (PCa), where androgen receptor (AR) is the primary oncogenic driver, epigenetic coregulators, specifically lysine demethylases (KDMs), have previously been identified as factors that alter the transcriptome as cancer cells acquire resistance. KDM7A has been identified as a cancer-promoting factor in many cancers; however, its role in PCa remains largely unexplored. This study investigates the clinical relevance of KDM7A in comparison with the well-studied KDM1A in PCa. Using PCa cell line models, we confirm KDM7A as an AR coregulator. By exploiting commercially available pharmacological inhibitors, we demonstrate that in AR-positive CRPC cell lines, combinatory inhibition of KDM1A and KDM7A leads to a loss of AR and the AR-driven transcriptome, which in turn attenuates cancer-promoting cell phenotypes. These findings highlight the potential of combination-targeted therapies in tackling advanced prostate cancers.

Keywords:  Lysine demethylases; androgen receptor; castration resistant prostate cancer (CRPC); co‐regulation; epigenetics; therapeutics

DOI:  https://doi.org/10.1002/1878-0261.70238
Curr Issues Mol Biol. 2026 Feb 27. pii: 258. [Epub ahead of print]48(3):

Genistein-Butein Co-Treatment Suppresses Glycolytic Metabolism and Induces Apoptotic Signaling in PC-3 Prostate Cancer Cells.

Moon-Kyun Cho, Yeji Lee, Sang-Han Lee, Hae-Seon Nam, Yoon-Jin Lee.

  Prostate cancer progression involves metabolic reprogramming that supports sustained proliferation and survival, highlighting metabolic pathways as potential targets for intervention. While genistein (GEN) and butein (BTN) are naturally occurring polyphenolic compounds with reported anticancer activities, their combined effects on prostate cancer cell metabolism and apoptotic signaling remain unclear. Here, we investigated the effects of GEN and BTN, administered individually and in combination, on human PC-3 prostate cancer cells, with normal human prostate epithelial cells (HPrEC) used for comparison. Cell viability was assessed using MTT and trypan blue exclusion assays. Glycolytic metabolism was evaluated by measuring glucose consumption, lactate production, hexokinase and pyruvate dehydrogenase activity, and intracellular ATP levels, while apoptotic and survival signaling pathways were analyzed by means of Annexin V staining and Western blotting. GEN/BTN co-treatment selectively reduced PC-3 cell viability, producing greater inhibitory effects than either compound alone. This enhanced response was accompanied by suppression of glycolytic metabolism, ATP depletion, attenuation of AKT and ERK phosphorylation, and activation of apoptotic signaling, as evidenced by increased cleavage of caspase-3 and PARP. Collectively, these findings indicate that GEN/BTN co-treatment cooperatively disrupts glycolytic metabolism while activating apoptotic signaling in prostate cancer cells.

Keywords:  PC-3 cells; apoptotic signaling; butein; combination treatment; genistein; glycolytic metabolism; prostate cancer

DOI:  https://doi.org/10.3390/cimb48030258
Front Pharmacol. 2026 ;17 1770261

A network pharmacology-guided multi-omics and spatial single-cell framework nominates WT1 as a spironolactone-linked immune biomarker in prostate cancer.

Zhen Zhu, Xingjun He.

   Introduction: Spironolactone (SPI), a mineralocorticoid receptor antagonist with anti-androgenic activity, has emerged as a candidate for drug repurposing in prostate cancer (PCa). However, the cellular pharmacology governing its impact on the tumor microenvironment and specific molecular targets remains incompletely understood. This study aims to elucidate the regulatory circuitry linking SPI to immune modulation and tumor suppression in the PCa ecosystem.
Methods: We employed an integrated framework combining network pharmacology with bulk, single-cell (scRNA-seq), and spatial transcriptomics (ST) to prioritize SPI-associated targets and map their microenvironmental context. The clinical and immunological relevance of the top candidate, Wilms Tumor 1 (WT1), was assessed using TCGA and GEO datasets. Finally, molecular docking and in vitro gain-of-function assays (proliferation, migration, clonogenicity, and apoptosis) in DU145 and PC-3 cell lines were conducted to validate functional mechanisms.
Results: Network pharmacology identified WT1 as a central regulatory node in the SPI-PCa interaction network. In clinical cohorts, WT1 was significantly downregulated in tumor tissues compared to normal prostate; however, preserved high WT1 expression correlated with improved disease-free survival. Crucially, WT1-high tumors exhibited an "immune-hot" phenotype characterized by enhanced T-cell infiltration and antigen presentation pathways. scRNA-seq and ST analyses revealed that WT1 is heterogeneously expressed across malignant and stromal compartments, localizing to specific immune-interacting niches. Molecular docking suggested a potential structural compatibility between SPI and WT1, although direct binding remains to be experimentally confirmed. Functionally, restoring WT1 expression in PCa cells potently suppressed malignant behaviors, inhibiting proliferation and migration while triggering apoptosis.
Conclusion: This study defines a novel SPI-WT1 axis, positioning WT1 as a druggable, immune-correlated biomarker in prostate cancer. By linking SPI pharmacology to WT1-associated microenvironmental features and tumor suppression, our findings provide a mechanistic rationale for repurposing Spironolactone as an immunomodulator to overcome therapeutic resistance in genitourinary oncology.

Keywords:  WT1; prostate cancer; single-cell; spironolactone; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2026.1770261
Cancers (Basel). 2026 Mar 19. pii: 998. [Epub ahead of print]18(6):

The Role of Gut Microbiome in Prostate Cancer: Current Evidence and Emerging Opportunities.

Jing Huang, Xin-Hua Zhu, Lloyd C Trotman, Che-Kai Tsao.

  Prostate cancer (PCa) is one of the most common malignancies in men, and growing evidence implicates the gut microbiome as a significant, modifiable contributor to disease evolution and management. Dysbiosis influences PCa biology through effects on inflammation, immune regulation, metabolism, and hormone signaling. Microbial imbalance can promote systemic inflammation and increase intestinal permeability, activating immune signaling pathways such as NF-κB-IL-6-STAT3. In parallel, microbiome-driven metabolic effects, including IGF-1 signaling and microbial androgen synthesis or recycling, may contribute to resistance to androgen deprivation therapy (ADT). Microbial metabolites, notably short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO), exert context-dependent effects on tumor growth, treatment resistance, and progression. Conversely, beneficial microbes have been associated with improved treatment sensitivity and immune regulation. Together, these insights support the gut microbiome as a potential biomarker and emerging therapeutic target in PCa. Modulation strategies, including diet, probiotics, antibiotics, and fecal microbiota transplantation (FMT), are being explored to improve treatment response and address resistance. As mechanistic evidence continues to grow, ongoing monitoring of the gut microbiome may help inform risk stratification and treatment optimization in prostate cancer.

Keywords:  androgen deprivation therapy (ADT); dysbiosis; gut microbiome; inflammation; prostate cancer; short-chain fatty acids (SCFAs)

DOI:  https://doi.org/10.3390/cancers18060998
Am J Cancer Res. 2026 ;16(2): 520-539

Phellinus linteus polysaccharides inhibit castration-resistant prostate cancer progression possibly via dual modulation of PIK3R1 and PGC-1α: a preclinical evaluation.

Wei Wei, Jingyi Huang, Le Xie, Zhanping Xu, Canbin Lin, Ming Chen.

  Castration-resistant prostate cancer (CRPC) remains a major challenge due to limited treatment options and frequent therapeutic resistance. This study demonstrates that Phellinus linteus polysaccharides (PLP), both in the form of drug-loaded serum and as a purified extract, exhibit potent anti-CRPC activity through a dual-axis molecular mechanism. In a castrated PC-3 xenograft model, PLP (400 mg/kg/day) suppressed tumor volume growth by 91.7% and tumor weight growth by 78.0% compared with the control group, showing efficacy comparable to abiraterone/prednisone without hepatorenal toxicity. In vitro, both 30% PLP-containing serum and purified PLP inhibited proliferation, migration, and invasion, and promoted apoptosis while reducing intracellular reactive oxygen species levels in PC-3 and 22RV1 cells. Integrative transcriptomic and multi-omics analyses revealed coordinated downregulation of phosphatidylinositol 3-kinase-protein kinase B-mechanistic target of rapamycin signaling and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Functional validation showed that overexpression of phosphoinositide-3-kinase regulatory subunit 1 rescued PLP-induced tumor suppression, whereas knockdown of PGC-1α abolished its antioxidative and antiproliferative effects, indicating that both pathways are critically involved. These findings suggest that PLP combats CRPC by simultaneously inhibiting oncogenic signaling and mitigating oxidative stress, positioning it as a promising natural therapeutic candidate for CRPC.

Keywords:  Castration-resistant prostate cancer; PGC-1α; PIK3R1; Phellinus linteus polysaccharides

DOI:  https://doi.org/10.62347/MJNQ6221
Int Immunopharmacol. 2026 Mar 20. pii: S1567-5769(26)00389-9. [Epub ahead of print]177 116544

LAMC3 promotes the development of prostate cancer via modulating the cell cycle progression.

Lei Chen, Ziqi Chen, Hekang Ding, Qintao Ge, Lingfan Xu, Jun Zhou, Huihui Wang, Chaozhao Liang.

   BACKGROUND: The senescence-associated secretory phenotype (SASP) plays a critical yet complex role in the progression of prostate cancer (PCa). Although multiple SASP components have been implicated in tumor development, the precise molecular mechanisms through which LAMC3 contributes to PCa pathogenesis remain incompletely understood.
MATERIALS AND METHODS: We conducted a comprehensive analysis of SASP components in serum samples from patients with PCa and benign prostatic hyperplasia (BPH) controls. A SASP-related gene signature was established and subsequently validated using nine bulk RNA-seq datasets and two single-cell RNA-seq cohorts. CCK-8, colony formation, EdU assays, etc., were performed to explore the roles of intrinsic LAMC3 on PCa as well as the underlying regulatory pathway.
RESULTS: SASP components were altered between PCa patients and BPH subjects, and the established SASP prognostic model exhibited good performance in patients' prognosis prediction. LAMC3 levels were significantly upregulated in PCa compared to BPH controls. Knockdown of LAMC3 markedly inhibited cellular proliferation, clonogenic potential, and cell cycle progression by inducing G1/S phase arrest. The PI3K/Akt pathway was inhibited after LAMC3 was suppressed, leading to the downregulation of CDKN1A (p21) and CDKN1B (p27) and causing cell cycle arrest. In vivo experiments demonstrated that LAMC3 silencing effectively suppressed tumor growth, and combination therapy with a PI3K inhibitor resulted in synergistic antitumor effects.
CONCLUSION: The intrinsic LAMC3 promotes prostate cancer progression, and LAMC3 is a key regulator of cell cycle progression in PCa, which was a therapeutic target for PCa management.

Keywords:  Cell cycle; LAMC3; PI3K; Prostate cancer; siRNA-targeting therapy

DOI:  https://doi.org/10.1016/j.intimp.2026.116544
Cell Death Discov. 2026 Mar 25.

SMARCA4 promotes lineage plasticity and enzalutamide resistance in prostate cancer by regulating PROX1 via H3K27 acetylation.

Chenwei Wu, Mayao Luo, Chaojian Wu, Yi Yuan, Yadong Li, Yuanpeng Liao, Yifan Zhang, Xin Huang, Mengqi Wang, Shidong Lv, Qiang Wei.

Enzalutamide resistance is a dynamic process often culminating in the aggressive progression to neuroendocrine prostate cancer (NEPC). This lineage plasticity is hypothesized to be driven by underlying epigenetic alterations, yet the core molecular drivers remain unclear. Elucidating these factors is of significant clinical importance for overcoming resistance. To model this transition, we established a dynamic gradient-resistant cell model simulating the clinical response to enzalutamide, and found robust upregulation of the chromatin remodeling factor SMARCA4 in resistant cells. Both in vitro and in vivo experimental results demonstrated that inhibiting SMARCA4 effectively suppresses tumor progression and reverses neuroendocrine transformation. Mechanistically, integrated multi-omics analysis, correlation studies, and protein interaction experiments revealed the transcription factor PROX1 as a crucial downstream target of SMARCA4, where its inhibition alone was sufficient to reverse the aggressive malignancy and neuroendocrine characteristics of resistant cells. We further demonstrated that SMARCA4 enhances H3K27ac levels and chromatin accessibility at the PROX1 locus to regulate its expression. Importantly, the tumor-suppressive effect of SMARCA4 knockdown could be rescued by histone deacetylase inhibitors (HDACi), achieving a level of recovery comparable to PROX1 overexpression. In summary, this study defines a core epigenetic pathway, showing that increased SMARCA4 activity promotes luminal-to-neuroendocrine transformation by enhancing histone acetylation and chromatin accessibility at the PROX1 locus. Targeting the SMARCA4-PROX1 axis provides a valuable therapeutic strategy for combating enzalutamide resistance and NEPC progression.

DOI: https://doi.org/10.1038/s41420-026-03068-0
Oncogene. 2026 Mar 23.

Aryl hydrocarbon receptor is critical for both AR-dependent and AR-indifferent enzalutamide resistance in castration-resistant prostate cancer.

Chia-Hui Chen, Ryan Brown, Donald J Vander Griend, Allen C Gao, Boyang Jason Wu.

The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistance to these therapies often develops rapidly, and the underlying resistance mechanisms remain largely unclear. Here, we identified the aryl hydrocarbon receptor (AHR) as a crucial operator of ENZ-resistant CRPC. AHR is upregulated in three ENZ-resistant human CRPC cell lines (C4-2BENZR, CWR-R1ENZR, and VCaPENZR) as well as in high-grade prostate tumors from patients receiving ENZ treatment. Stable knockdown of AHR substantially reduced the growth of ENZ-resistant CRPC cells and xenografts. Mechanistically, AHR engages in distinct transcriptional programs in a cellular context-dependent manner. AHR directly regulates the transcription and expression of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes in CWR-R1ENZR cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2BENZR cells, indicating an AR-indifferent mechanism of ENZ resistance. The diverse mechanisms triggered by ENZ were also manifested in clinical samples. Collectively, these findings characterize AHR's contribution to ENZ resistance in CRPC and illuminate the potential of targeting AHR for treating ARSI-resistant advanced prostate cancer.

DOI: https://doi.org/10.1038/s41388-026-03723-x
Discov Oncol. 2026 Mar 22.

Probing uric acid-related prognostic genes and their molecular mechanisms in prostate cancer based on transcriptomic data.

Xin Liu, Xiaodong Yan, Xinyang Zhao, Hongwei Su, Haibin Ling, Xiangdong Li.

  Recent studies highlight the role of uric acid in tumor development, but its impact on prostate cancer (PCa) remains underexplored. This study aimed to investigate how uric acid influences PCa prognosis by analyzing transcriptomic data on PCa and uric acid-related genes (UARGs) from public databases. Differential expression analysis, protein-protein interaction (PPI) network, univariate Cox regression, and machine learning were used to identify prognostic genes. A risk model was then constructed based on these genes. Six prognostic genes (AHSG, AOX1, APOC1, LPL, NKX2-2, NKX6-1) were identified through the analysis of 1 433 differentially expressed genes (DEGs) and 3 806 UARGs. The risk model showed strong predictive ability, with the high-risk group (HRG) exhibiting poorer prognosis. Additionally, 10 immune cell types were significantly different between risk groups, with the HRG showing higher tumor mutation burden. A total of 8 drugs were found to correlate with risk scores. Enrichment analysis revealed that AHSG, AOX1, and APOC1 were linked to oxidative stress and Parkinson's disease, while NKX2-2 and NKX6-1 were associated with RNA degradation. These findings suggest that oxidative stress may be a key mechanism in PCa progression. This study offers a novel perspective on PCa treatment by identifying 6 prognostic genes and providing a prognostic risk model.

Keywords:  Prognostic genes; Prostate cancer; Risk scores; Uric acid

DOI:  https://doi.org/10.1007/s12672-026-04874-9
Apoptosis. 2026 Mar 22. pii: 109. [Epub ahead of print]31(4):

Insulin-like growth factor binding protein-3 serves as a biomarker for resistance to enzalutamide in prostate cancer.

Ze Gao, Bingzheng An, Shuo Chen, Yifan Wang, Liwei Meng, Kefan Song, Ulf Schmitz, Ning Zhang, Zhiqing Fang.

  Enzalutamide resistance (EnzR) is a major challenge in the current treatment of castration-resistant prostate cancer, as tumors frequently progress to drug resistance after an initially effective treatment. Therefore, there is an urgent need to characterize the genes alterations that accompany EnzR in prostate cancer and to identify new therapeutic targets. In this study, we analyzed a total of 1273 publicly available transcriptomics datasets from patients who underwent prostate cancer surgery. We investigated transcriptomic changes after enzalutamide (ENZ) treatment, identified key genes involved in the process of EnzR, and developed EnzR scores to predict tumor progression. We further investigated the role of IGFBP3 in the regulation of EnzR in prostate cancer. The effect of IGFBP3 expression level on the malignant degree of EnzR cells was explored in vitro. In addition, we explored the downstream mechanism of IGFBP3 involvement in EnzR. We found that epithelial-mesenchymal transition (EMT), cancer stem cell-like properties, and neuroendocrine transformation occurred in tumor cells after ENZ treatment. Subsequently, we developed and validated EnzR scores to predict prostate cancer tumor progression. Furthermore, we experimentally confirmed that IGFBP3 promotes the proliferation of drug-resistant cells and enhances ENZ resistance via EMT signaling. Overall, we established a new EnzR scoring model through multidimensional analysis of EnzR patterns. This model can accurately predict the clinical prognosis of prostate cancer patients after surgery. Moreover, IGFBP3 can be used as a potential therapeutic target for ENZ resistance in prostate cancer.

Keywords:  Enzalutamide resistance; IGFBP3; Prostate cancer

DOI:  https://doi.org/10.1007/s10495-026-02318-x
Mol Cell Biochem. 2026 Mar 27.

USP52 impedes malignant progression and cell stemness in prostate cancer by deubiquitinating RBM5 to down-regulate NCAPG2.

Hongliang Wu, Sheng Wang, Shuai Yang, Wenyan Sun, Han Guan.

  Ubiquitin-specific protease 52 (USP52) is vital to cancer progression by mediating the deubiquitination; however, its biological role and mechanism in prostate cancer (PCa) remain unexplored. Herein, this study aimed to discover the functional regulation of USP52 with RNA binding motif protein 5 (RBM5) and non-SMC condensin II complex subunit G2 (NCAPG2) in PCa development and stemness. RT-qPCR and Western blot were applied for expression analysis. Proliferation was assessed by colony formation and EdU assays. Cell metastasis was measured by wound healing migration assay and transwell invasion assay. Cell stemness was detected via sphere formation assay, flow analysis and Western blot detection. USP52 function in tumor growth in vivo was investigated by xenograft tumor assay. Co-immunoprecipitation was conducted for ubiquitination detection. Interaction between RBM5 and NCAPG2 was examined using dual-luciferase reporter assay. PCa samples and cells exhibited the aberrant downregulation of USP52. USP52 overexpression suppressed PCa cell proliferation, migration, invasion and stemness. PCa tumor growth in vivo was hindered by USP52. USP52 stabilized RBM5 protein expression in PCa cells by acting as a deubiquitinating enzyme. RBM5 interacted with NCAPG2 3'UTR and USP52 could down-regulate NCAPG2. USP52 repressed PCa cell progression and stemness via reducing NCAPG2. Thus, USP52 hampered PCa cell development and stemness through removing ubiquitination of RBM5 to control the expression of NCAPG2. USP52 may be used as a therapeutic target for PCa.

Keywords:  Cell stemness; Non-SMC condensin II complex subunit G2; Prostate cancer; RNA binding motif protein 5; Ubiquitin-specific protease 52

DOI:  https://doi.org/10.1007/s11010-026-05522-0
Anticancer Res. 2026 Apr;46(4): 1929-1942

Paired-sample Analysis of ERG Expression and TMPRSS2-ERG Fusion in Treatment-induced Neuroendocrine Prostate Cancer.

Chu-shikoku Japan Urological Consortium (CsJUC) Research Collaboration

   BACKGROUND/AIM: Prostate cancer is one of the most common malignancies in men. Although androgen deprivation therapy (ADT) offers substantial benefit, resistance to androgen signaling ultimately develops, leading to castration-resistant prostate cancer (CRPC). Approximately 10-17% of CRPC cases evolve into treatment-induced neuroendocrine prostate cancer (t-NEPC), an aggressive, androgen receptor (AR)-independent subtype. The TMPRSS2-ERG fusion gene is among the most frequent genomic alterations in prostate cancer; however, its involvement in t-NEPC development remains unclear.
PATIENTS AND METHODS: We retrospectively analyzed nine Japanese cases of t-NEPC diagnosed across multiple institutions. Immunohistochemical staining for AR and ERG and RT-PCR for TMPRSS2-ERG fusion gene expression were performed on paired adenocarcinoma and t-NEPC samples. Clinical data - including prostate specific antigen levels, Gleason scores, metastatic patterns, and outcomes - were compared between ERG-positive and ERG-negative groups.
RESULTS: ERG-positive prostate cancer was found in three of nine cases (33.3%), all of which were AR-positive, indicating that active AR signaling is required for TMPRSS2-ERG expression. ERG positivity was not clearly associated with prognosis or drug sensitivity, but time to NEPC differentiation tended to be shorter in ERG-positive cases. Only the e1e4 isoform of TMPRSS2-ERG was detected, while e2e4 was absent.
CONCLUSION: This study highlights heterogeneity in TMPRSS2-ERG fusion dynamics during t-NEPC evolution and suggests a potential association between ERG expression and earlier NE differentiation. This study provides a rare opportunity to analyze paired pre- and post-NEPC tissues, offering valuable insight into the relationship between ERG and TMPRSS2-ERG fusion gene expression and clinical parameters.

Keywords:  AR-pathway positive prostate cancers (ARPC); ERG expression; TMPRSS2-ERG fusion gene; treatment induced NEPC (t-NEPC)

DOI:  https://doi.org/10.21873/anticanres.18085
Angew Chem Int Ed Engl. 2026 Mar 23. e6657773

Nanozyme-Mediated PROTACs Delivery for Targeted Protein Degradation and Ferroptosis Sensitization in Prostate Cancer.

Chenyuan Wang, Xue Jiang, Jiapeng Lei, Wen Zhang, Fuqiang Shao, Tianshu Hao, Yongnian Zeng, Peng Jiang, Fan Cheng, Lingqi Liu, Wei Li.

  Castration-resistant prostate cancer (CRPC) remains a major clinical challenge due to its resistance to conventional androgen receptor (AR)-targeted therapies. Proteolysis-targeting chimeras (PROTACs) drugs, such as ARV-771, can selectively degrade cancer-driving proteins but face major delivery challenges that limit their efficacy and safety. Here, we report a nanoengineered PROTAC platform, ARV@MIL-HA-ss-HA, that markedly improves ARV-771 delivery, pharmacokinetics, and therapeutic efficacy. The system employs MIL-101 nanoparticles as both a carrier and a nanozyme, modified with hyaluronic acid-disulfide-hyaluronic acid (HA-ss-HA) hydrogel to achieve CD44-mediated tumor targeting and glutathione (GSH)-triggered release. Leveraging the catalytic activity of MIL-101 and the GSH-depleting capacity of HA-ss-HA, ARV@MIL-HA-ss-HA converts intracellular H2O2 into hydroxyl radicals (·OH) and suppresses GSH levels, thereby inducing ferroptosis. Concurrently, ARV-771-mediated BRD4 degradation sensitizes tumor cells to ferroptosis, establishing a dual-action synergistic mechanism. In vitro and in vivo studies in CRPC models confirmed efficient BRD4 degradation, enhanced ferroptotic cell death, and superior antitumor efficacy with minimal systemic toxicity. Our findings position this nano-PROTAC strategy as a clinically promising dual-mechanism therapy capable of overcoming resistance in CRPC.

Keywords:  PROTACs; ferroptosis; prostate cancer; synergistic sensitization; target therapy

DOI:  https://doi.org/10.1002/anie.6657773
J Cell Mol Med. 2026 Apr;30(7): e71101

Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage.

Aishwarya Gondane, Shivani Yalala, Jing Liang, Sonja Saira, Harri M Itkonen.

  Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes a subset of prostate cancers but it is not understood how cells adapt to declining activity of this major transcription elongation kinase. To probe this response, we developed a cell line resistant to an inhibitor targeting CDK12 and its paralog, CDK13. CDK13 can compensate for the loss of CDK12, which is why we used the dual inhibitor THZ531. Targeted drug screening of the parental and resistant cell lines revealed cross-resistance to other transcriptional kinases but no clear acquired point of vulnerability. Using genome-wide mapping of mRNA-stabilization based on metabolic labelling of RNA, we report selective mRNA stabilization of factors promoting oxidative phosphorylation in the resistant cells. We go on to show that loss of CDK12 activity enhances ATP production both in cell line models and in patient tumours. Finally, we show that dual inhibition of CDK12/13 results in excessive phosphorylation of the DNA damage H2AX in prostate cancer cells but not in our CDK12/13 inhibitor-resistant model system. In brief, we propose that inactivation of CDK12 rewires cellular energy metabolism to suppress DNA damage.

Keywords:  SLAM‐seq; acquired resistance; cyclin‐dependent kinase 12; genomic instability; metabolism; prostate cancer; transcription elongation

DOI:  https://doi.org/10.1111/jcmm.71101
Antioxidants (Basel). 2026 Mar 20. pii: 393. [Epub ahead of print]15(3):

Quercetin Inhibits AKT Ser473 Phosphorylation and Disrupts AKT-Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Cells.

Félix Duprat, Sebastián Azócar-Plaza, María Paz Castillo-Cáceres, Yerko Rivas, Javiera Sanzana-Rosas, Paolo Pampaloni, Gabriel Olivas-Henríquez, Jorge Toledo, Jhon López Villa, Romina Bertinat, Nery Jara, Alejandro Vallejos-Almirall, Alexis Salas, Iván González-Chavarría.

  The progression of prostate cancer to castration-resistant disease (CRPC) remains a clinical challenge in which oxidative stress intersects with the PI3K/AKT-androgen receptor (AR) axis. Quercetin (QRC) is a redox-active dietary flavonol, yet its mechanistic impact on CRPC is incompletely defined. Here, we tested whether QRC suppresses AR output by directly modulating AKT. C4-2B and 22Rv1 CRPC cell lines were treated with increasing QRC concentrations, with or without enzalutamide (Enz). Proliferation and viability were monitored by IncuCyte imaging and SYTOX Green incorporation. AKT phosphorylation (S473), AR phosphorylation (S210/213), AR abundance and localization, and prostate-specific antigen (PSA) secretion were assessed by immunoblotting, immunofluorescence, and dot blot, respectively. Docking and molecular dynamic simulations were performed to identify and evaluate a putative QRC-binding site on AKT. QRC produced a dose-dependent cytostatic effect (IC50 24.37 μM in C4-2B; 21.54 μM in 22Rv1) without marked cell death, reduced pAKT(S473) by up to 80%, decreased pAR(S210/213), and diminished nuclear AR and PSA secretion. Simulations suggested a putative druggable allosteric pocket in the AKT1 N-lobe, with G159 emerging as a potential anchor residue. Enz cotreatment with QRC did not produce additive effects, consistent with a model in which QRC acts upstream of ligand-driven AR activation and thereby limits the incremental benefit of AR antagonism under these conditions. These data support QRC as an AKT-AR axis modulator in CRPC and provide a target engagement framework beyond simple ROS scavenging.

Keywords:  PI3K/AKT; PSA; androgen receptor; castration-resistant prostate cancer; enzalutamide; quercetin

DOI:  https://doi.org/10.3390/antiox15030393
Cancers (Basel). 2026 Mar 11. pii: 899. [Epub ahead of print]18(6):

Hypoxia-Driven Mechanisms of Drug Resistance in Prostate Cancer.

Madeline R Ressel, Caitlyn E Flores, Noel A Warfel.

  Prostate cancer is the most common non-cutaneous malignancy in men and is the second leading cause of male cancer-related mortality. Unlike many cancers, prostate cancer lacks clear genetic driver mutations, suggesting that factors in the tumor microenvironment contribute to the genesis and progression of this disease. Hypoxia, or a physiological state of low oxygen, is a universal characteristic of solid tumors that enhances disease progression and therapeutic resistance. Prostate cancer develops in a hypoxic microenvironment and primarily metastasizes to bone, where oxygen availability is similarly limited. Therefore, hypoxia is a major obstacle to the effective treatment of prostate cancer across all disease stages. Clinically, hypoxia is correlated with worse patient outcomes, largely because it drives resistance to the frontline therapies used to treat both primary and metastatic prostate cancer. Despite the established role of hypoxia in prostate cancer progression and drug resistance, it has not been successfully targeted therapeutically. Emerging evidence indicates that exposure to distinct temporal patterns of hypoxia (acute, cyclic, and chronic) elicits unique cellular adaptations that dictate tumor growth and survival. This review synthesizes current evidence regarding the role of hypoxia in promoting resistance to therapy in prostate cancer.

Keywords:  CRPC; bone metastasis; hypoxia; prostate cancer; therapeutic resistance

DOI:  https://doi.org/10.3390/cancers18060899
Cancer Res. 2026 Mar 25. OF1-OF18

Single-Cell and Spatial Transcriptomic Profiling Reveals Epithelial Functional States and Fibroblast Phenotypes in Hormone Therapy-Naïve Localized Prostate Cancer.

Eva Apostolov, Daniel L Roden, Holly Holliday, Aurélie Cazet, Kate Harvey, Hanyun Zhang, Sunny Z Wu, Sophie van der Leij, Hani Jieun Kim, Luke A Selth, Nenad Bartonicek, Ghamdan Al-Eryani, John L Reeves, Mengxiao He, Joakim Lundeberg, Alison J Potter, James G Kench, Phillip D Stricker, Anthony M Joshua, Lisa G Horvath, Alexander Swarbrick.

Localized prostate cancers are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumor microenvironment (TME). To further characterize the heterogeneity of the TME, we performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naïve localized prostate cancer using single-cell RNA sequencing (scRNA-seq). Integrating copy-number variation and transcriptional signatures enabled epithelial cell classification across a malignant spectrum, revealing widespread molecular perturbation. The analysis revealed patient-unique and shared luminal states and an expansion of club cell phenotypes, suggesting luminal dedifferentiation. Detailed annotation of stromal phenotypes, with a focus on fibroblasts, identified a perineural fibroblast population. Spatial transcriptomics elucidated the precise anatomic distribution of cancer-associated fibroblasts within the prostate cancer TME. Together, this study provides a valuable foundation for advancing the understanding of prostate cancer pathobiology and developing a comprehensive cellular model of the disease.
SIGNIFICANCE: Development of a single-cell RNA-sequencing and spatial transcriptomics cellular reference of localized prostate cancer enables identification of a spectrum of malignant epithelial phenotypes and discovery of a perineural class of fibroblast.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1202
Cell Commun Signal. 2026 Mar 28.

The hexosamine biosynthetic pathway alters the cytoskeleton to modulate cell proliferation and migration in aggressive prostate cancer.

Rajina Shakya, Praveen Suraneni, Amit Rahi, Michael Young, Emily Cousino, Christine B Magdongon, Raju Gajjela, Basil B Mattamana, Alexander Zaslavsky, Ganesh S Palapattu, Arun Sreekumar, Dileep Varma.

  Castration-resistant prostate cancer (CRPC) progresses despite androgen deprivation therapy, as cancer cells adapt to grow without testosterone, becoming more aggressive and prone to metastasis. CRPC biology complicates the development of effective therapies, posing challenges for patient care. Recent gene-expression and metabolomics studies highlight the Hexosamine Biosynthetic Pathway (HBP) as a critical player, with key components like GNPNAT1 (Glucosamine-phosphate N-acetyltransferase 1) being downregulated in CRPC. GNPNAT1 knockdown in pre-clinical models has been shown to increase growth and metastasis in CRPC tumors, though the mechanisms remain unclear.To investigate the cellular basis of these CRPC phenotypes, we generated a CRISPR-Cas9 knockout model of GNPNAT1 in 22Rv1 CRPC cells, analyzing its impact on transcriptomic and glycoproteomic profiles of cells. We find that HBP inhibition disrupts the cytoskeleton, altering mitotic progression and promoting uncontrolled growth. GNPNAT1 KO cells showed reduced levels of cytoskeletal filaments, such as actin and microtubules, leading to cell structure disorganization and chromosomal mis-segregation. GNPNAT1 inhibition also activated PI3K/AKT signaling, promoting cell proliferation, impaired cell adhesion by mis-localizing Eph Receptor B6, enhancing migration via the RhoA (Ras homolog family member A) pathway and promoting epithelial-to-mesenchymal transition. These findings suggest that HBP plays a critical role in regulating CRPC cell behavior, and targeting this pathway could provide a novel therapeutic approach.

Keywords:  Cell migration; Cell proliferation; Cell signaling; Cytoskeleton; Hexosamine biosynthetic pathway; Metastatic prostate cancer; Mitosis

DOI:  https://doi.org/10.1186/s12964-026-02756-9
Cancer Manag Res. 2026 ;18 573379

Adaptation of MALDI-TOF MS Technique for Tracking Changes in the Urinary Microbiome During and After Radiotherapy for Prostate Cancer.

Michał Złoch, Ewelina Sibińska, Fernanda Monedeiro, Wioletta Miśta, Adrian Arendowski, Piotr Fijałkowski, Monika Pietrowska, Jolanta Mrochem-Kwarciak, Anna Jędrzejewska, Ewa Telka, Kinga Karoń, Małgorzata Rabsztyn, Paweł Pomastowski, Dorota Gabryś.

   Purpose: The urinary microbiome may influence the development of radiation-induced complications in prostate cancer. However, its dynamics during and after radiotherapy (RT) remain unclear. This study aimed to use matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to characterize and monitor urinary microbiome changes during RT for prostate cancer.
Patients and Methods: Eighty-eight patients with prostate cancer who underwent RT were included. Midstream urine and blood samples were collected at six time points: before gold fiducial implantation (t1), at the start (t2) and end of RT (t3), and at 1, 4, and 7 months post-RT (t4-t6). Microorganisms were cultured under diverse conditions and identified by MALDI-TOF MS. Statistical analyses were used to assess the associations between microbial profiles, RT stages, and biochemical parameters in the urine and blood.
Results: A total of 1773 microbial isolates were identified in 89% of urine samples, with 79% showing a polymicrobial composition. The microbiota was dominated by Staphylococcus (51.6%), Micrococcus, Enterococcus, Kocuria, and Corynebacterium. Biodiversity decreased at the end of RT but gradually recovered up to seven months post-treatment. Genera such as Actinomyces, Corynebacterium, Staphylococcus, and Streptococcus were significantly correlated with study time course, whereas the abundance of Kocuria rhizophila increased over time. Changes in microbiome composition were strongly associated with glucose levels in urine and blood.
Conclusion: RT triggers a dynamic response in the urinary microbiome, with an initial decline in diversity followed by progressive recolonization. Glucose levels in urine and blood significantly affect microbial composition, suggesting that metabolic factors modulate RT-related microbiome shifts. These findings highlight the interplay between RT, host metabolism, and urinary microbiota, supporting the potential value of glucose monitoring to maintain microbial balance after RT.

Keywords:  MALDI; microbiome; prostate cancer; radiotherapy; urinary microbiota; urine

DOI:  https://doi.org/10.2147/CMAR.S573379