bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–06–29
fourteen papers selected by
Grigor Varuzhanyan, UCLA
  1. Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.
  2. TMPRSS2-ERG confers resistance to antiandrogens: mechanism and therapeutic implications.
  3. Hypoxia induced lipid droplet accumulation promotes resistance to ferroptosis in prostate cancer.
  4. Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies.
  5. Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a Target for Antibody-Drug Conjugate Therapy.
  6. In silico identification of PPARγ agonists from diffractaic acid analogs in prostate cancer: a comprehensive computational approach.
  7. ELOVL2 mediated stabilization of AR contributes to enzalutamide resistance in prostate cancer.
  8. Bioinformatics-Driven Engineering of ROS-Responsive Dextran-block-Poly(propylene sulfide) Nanoparticles Functionalized with Folic Acid for Targeted Prostate Cancer Therapy.
  9. Lactylation-Related Gene LILRB4 Predicts the Prognosis and Immunotherapy of Prostate Cancer Based on Machine Learning.
  10. Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer.
  11. A Novel Three Small Molecule Inhibitor Combination Therapy For Prostate Cancer.
  12. BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer.
  13. Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer.
  14. Identification of autophagy-related biomarkers in prostate cancer prognosis.
  1. Cancers (Basel). 2025 Jun 12. pii: 1959. [Epub ahead of print]17(12):
    Steroid Sulfatase Regulates Metabolic Reprogramming in Advanced Prostate Cancer.
    Masuda Sharifi, Cameron M Armstrong, Shu Ning, Amy R Leslie, Zachary A Schaaf, James P Maine, Wei Lou, Pui-Kai Li, Hongyu Xu, Chengfei Liu, Allen C Gao.
       BACKGROUND/OBJECTIVE: The expression of human steroid sulfatase (STS) is upregulated in castration-resistant prostate cancer (CRPC) and is associated with resistance to anti-androgen drugs, such as enzalutamide (Enza) and abiraterone (Abi). Despite the known link between STS overexpression and therapeutic unresponsiveness, the mechanism by which STS confers this phenotype remains incompletely understood. In this study, we sought to understand how STS induces treatment resistance in advanced prostate cancer (PCa) cells by exploring its role in altering mitochondrial activity.
    METHODS: To examine the effects of increased STS expression on mitochondrial respiration and programming, we performed RNA sequencing (RNA-seq) analysis, the Seahorse XF Mito Stress Test, and a mitochondrial Complex I enzyme activity assay in STS-overexpressing cells (C4-2B STS) and in enzalutamide-resistant CPRC cells (C4-2B MDVR). We employed SI-2, the specific chemical inhibitor of STS, on C4-2B STS and C4-2B MDVR cells and evaluated STS activity inhibition on mitochondrial molecular pathways and mitochondrial respiration. Lastly, we examined the effects of dehydroepiandrosterone sulfate (DHEAS) supplementation on C4-2B STS organoids.
    RESULTS: We present evidence from the transcriptomic profiling of C4-2B STS cells that there are enriched metabolic pathway signatures involved in oxidative phosphorylation, the electron transport chain, and mitochondrial organization. Moreover, upon STS inhibition, signaling in the electron transport chain and mitochondrial organization pathways is markedly attenuated. Findings from the Seahorse XF Mito Stress Test and mitochondrial Complex I enzyme activity assay demonstrate that STS overexpression increases mitochondrial respiration, whereas the inhibition of STS by SI-2 significantly reduces the oxygen consumption rate (OCR) and Complex I enzyme activity in C4-2B STS cells. Similarly, an increased OCR and electron transport chain Complex I enzymatic activity are observed in C4-2B MDVR cells and a decreased OCR upon SI-2 inhibition. Lastly, we show that STS overexpression promotes organoid growth upon DHEAS treatment.
    CONCLUSIONS: Our study demonstrates STS as a key driver of metabolic reprogramming and flexibility in advanced prostate cancer. Disrupting enhanced mitochondrial respiration via STS presents a promising strategy in improving CRPC treatment.
    Keywords:  metabolic reprogramming; prostate cancer; steroid sulfatase; therapeutic resistance
    DOI:  https://doi.org/10.3390/cancers17121959
  2. bioRxiv. 2025 Jan 20. pii: 2025.01.17.633582. [Epub ahead of print]
    TMPRSS2-ERG confers resistance to antiandrogens: mechanism and therapeutic implications.
    Arunachalam Sekar, Rishita Chatterjee, Boobash Raj Selvadurai, Lipika R Pal, Aakanksha Verma, Nishanth Belugali Nataraj, Diana Drago Garcia, Suvendu Giri, Alessandro Genna, Feride Karatekin, Nitin Gupta, Mirie Zerbib, Yaron Vinik, Tamir Avioz, Eviatar Weizman, Eyal David, Alejändro A Schaffer, Yunqian Pan, Haojie Huang, Wytske M van Weerden, Eva Corey, Hazel Hunt, Andrew E Greenstein, Ronnie Blecher-Gonen, Roni Oren, Ariel Afek, Ido Amit, Sima Lev, Anson Ku, Sumeyra Kartal, Jack R Bright, Rosina T Lis, William L Dahut, Adam G Sowalsky, Eytan Ruppin, Yosef Yarden.
      Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG , remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG -positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
    DOI:  https://doi.org/10.1101/2025.01.17.633582
  3. Oncotarget. 2025 Jun 25. 16 532-544
    Hypoxia induced lipid droplet accumulation promotes resistance to ferroptosis in prostate cancer.
    Shailender S Chauhan, Andres D Vizzerra, Hope Liou, Caitlyn E Flores, Ashley J Snider, Justin M Snider, Noel A Warfel.
      Ferroptosis is a mode of cell death that relies on iron metabolism and lipid peroxidation. Preclinical and clinical studies indicate that ferroptosis suppresses tumor growth, and dysregulation of ferroptosis promotes treatment resistance in cancer. Hypoxia is a universal feature of solid tumors that is particularly relevant to prostate cancer (PCa), which arises in the hypoxic peripheral zone of the organ. Hypoxia has been implicated in resistance to ferroptosis and other forms of cell death, but how hypoxia impacts the sensitivity of PCa to ferroptosis inducing agents (FINs) has not been well studied. Here, we show that hypoxia dramatically reduces the sensitivity of PCa cell lines to mechanistically distinct FINs, Erastin (xCT inhibitor) and RLS3 (GPX4 inhibitor) by inducing lipid droplet (LD) accumulation. Transcriptomic analysis revealed that hypoxia significantly reduced the expression of genes related to incorporating polyunsaturated fatty acids into phospholipids (ACSL4, LPCAT3), and parallel lipidomic analysis demonstrated that hypoxia significantly decreased the levels of the ferroptosis-prone lipid class, phosphatidylethanolamine (PE) and increased production of neutral lipid species, cholesteryl ester (ChE (22:5)) and triglycerides (TG(48:1), TG:(50:4), and TG(58:4)). Targeting LD biogenesis and de novo lipogenesis did not alter sensitivity to RSL3 under hypoxia. These findings suggest that hypoxia promotes ferroptosis resistance in PCa by altering lipid metabolism at the transcriptional level, by producing lipids that are less susceptible to peroxidation, and at the cellular level, by increasing storage in LDs. Thus, manipulating LD dynamics represents a promising strategy to overcome hypoxia-induced resistance to ferroptosis and improve the success of PCa treatment.
    Keywords:  ferroptosis; hypoxia; lipid droplets; prostate; resistance
    DOI:  https://doi.org/10.18632/oncotarget.28750
  4. Res Rep Urol. 2025 ;17 211-223
    Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies.
    Alberto Quistini, Francesco Chierigo, Giuseppe Fallara, Massimiliano Depalma, Marco Tozzi, Martina Maggi, Letizia Maria Ippolita Jannello, Francesco Pellegrino, Guglielmo Mantica, Daniela Terracciano, Rocco Papalia, Felice Crocetto, Rocco Damiano, Roberto Bianchi, Bernardo Maria Rocco, Matteo Ferro.
      Prostate cancer (PCa) is a major global health concern. It ranks as the fifth leading cause of cancer-related mortality worldwide. While localized PCa is often indolent, with a nearly 100% five-year survival rate, prognosis worsens significantly in metastatic disease, where survival drops to approximately 30%. Androgen deprivation therapy (ADT) is initially effective in suppressing tumor growth. However, resistance eventually develops, resulting in castration-resistant prostate cancer (CRPC). The androgen receptor (AR) plays a central role in both PCa progression and treatment resistance. It promotes tumor growth by mediating the effects of testosterone and 5α-dihydrotestosterone (DHT). Several mechanisms contribute to resistance. These include AR gene mutations that reduce ligand specificity or convert antagonists into agonists. AR overexpression can maintain activity even at low androgen levels. Splice variants such as AR-V7 can activate AR signaling despite androgen depletion. AR transcriptional activity is also modulated by coregulators. Coactivators (such as the SRC family) and corepressors (such as NCOR1/2) contribute to the persistence of AR signaling. Beyond AR-dependent mechanisms, CRPC may develop through AR-independent pathways. These include glucocorticoid receptor (GR) bypass signaling and lineage plasticity leading to neuroendocrine prostate cancer (NEPC). In addition, intratumoral steroidogenesis sustains AR activation despite systemic suppression of androgens. Together, these resistance mechanisms underscore the biological complexity of CRPC. They also highlight the urgent need for innovative therapeutic approaches. This manuscript reviews emerging molecular targets and resistance pathways to inform the development of next-generation treatments.
    Keywords:  ADT; AR; CRPC; androgen deprivation therapy; androgen receptor; castration-resistant prostate cancer; prostate cancer; therapeutic resistance
    DOI:  https://doi.org/10.2147/RRU.S388265
  5. JCI Insight. 2025 Jun 24. pii: e190924. [Epub ahead of print]
    Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a Target for Antibody-Drug Conjugate Therapy.
    Keisuke Shigeta, Tatsuaki Daimon, Hiroshi Hongo, Sheng-Yu Ku, Hiroki Ozawa, Naoki Haratake, Atsushi Fushimi, Ayako Nakashoji, Atrayee Bhattacharya, Shinkichi Takamori, Michihisa Kono, Masahiro Rokugo, Yuto Baba, Takeo Kosaka, Mototsugu Oya, Justine Jacobi, Mark D Long, Himisha Beltran, Donald W Kufe.
      Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) invariably become resistant to treatment with targeted and cytotoxic agents. Multiple pathways have been identified as being responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC/NEPC in association with poor clinical outcomes; whereas, it is not known if the oncogenic MUC1-C/M1C protein drives treatment resistance. We demonstrated that MUC1-C is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). Our results showed that MUC1-C-mediated resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species necessary for self-renewal. Dependence of these resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state identified a potential target for treatment. In this regard, we further demonstrated that targeting MUC1-C with a M1C antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC/NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings uncovered a common MUC1-C-dependent pathway in treatment-resistant CRPC/NEPC progression and identified MUC1-C as a target for their treatment with a M1C ADC.
    Keywords:  Cancer; Drug therapy; Oncology; Therapeutics; Urology
    DOI:  https://doi.org/10.1172/jci.insight.190924
  6. 3 Biotech. 2025 Jul;15(7): 219
    In silico identification of PPARγ agonists from diffractaic acid analogs in prostate cancer: a comprehensive computational approach.
    Miah Roney, Md Nazim Uddin, Azmat Ali Khan, Mohd Fadhlizil Fasihi Mohd Aluwi, Sabiha Fatima, Asrar Ahmad.
      Prostate cancer (PCa) is the second most frequent and the fifth greatest cause of death in men. Although there are already therapies for early-stage PCa, their effectiveness in advanced PCa is limited, primarily because of medication resistance or poor efficacy. To find new therapeutic indications or repurpose current medications, this project intends to use computational approaches to investigate possible anti-PCa compounds based on simulated screening of FDA-approved drug bank databases. The techniques used in this study include virtual screening of the drug bank database utilising a matrix or user molecule (Diffractaic acid; DA), integrated network pharmacology, molecular docking, detailed molecular dynamic simulation. The results showed that 18 DA analogues in total were chosen from the drug bank database and put through integrated network pharmacology. The KEGG enrichment analysis indicated that hsa05215: Prostate cancer is one of the most significant PCa enrichment signalling pathways which exhibited 18 protein-protein interactions including PDGFRB, PDGFRA, PPARG, GSK3B, MAP2K1, CREBBP, HSP90AA1, HSP90AB1, CHUK, PIK3CD, BRAF, PIK3CB, MTOR, AR, PIK3CA, PLAU, CDK2, and MAPK1. Subsequent molecular docking study with the best target protein (PPARγ) showed that the DB14929 molecule formed hydrogen bonds with the Gln273, Arg280, Arg288, and Ser342 residues and exhibited a high binding affinity ( - 10.5 kcal/mol) for the PPARγ agonist against PCa. Furthermore, molecular dynamic simulation showed that DB14929 formed a stable protein-ligand complex with RMSD, RMSF, Rg, and SASA values. Furthermore, the dynamic behaviour of the PPARγ protein linked to DB14929 in its conformational space was analysed using the PCA technique, demonstrating the excellent conformational space behaviour. Additionally, the free binding energy value of - 57.15 kcal/mol of DB14929 indicated that it could be an agonist of PPARγ of PCa.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04376-5.
    Keywords:  Diffractaic acid; Docking; MD simulation; Network pharmacology; PPARγ agonist; Prostate cancer
    DOI:  https://doi.org/10.1007/s13205-025-04376-5
  7. Front Cell Dev Biol. 2025 ;13 1598400
    ELOVL2 mediated stabilization of AR contributes to enzalutamide resistance in prostate cancer.
    Jinpeng Cen, Jiading Guo, Xianzi Zeng, Xianlu Song, Shengdong Ge, Mingkun Chen, Qianyi Li, Yuzhong Yu, Daojun Lv, Shanchao Zhao.
       Introduction: To investigate the molecular mechanisms underlying enzalutamide resistance in castration-resistant prostate cancer (CRPC) and explore potential therapeutic strategies to overcome resistance.
    Methods: We conducted comprehensive bioinformatic analysis using LNCaP/enzalutamide-resistant cells to identify key pathways associated with resistance. Functional validation was performed through targeted inhibition of the elongation of very-long chain fatty acid protein 2 (ELOVL2), followed by assays to assess cancer cell proliferation and enzalutamide sensitivity. Mechanistic studies were conducted to evaluate the impact of ELOVL2 on the ubiquitin-proteasome system and AR signaling pathways.
    Results: Bioinformatic analysis revealed that activation of fatty acid metabolism, particularly through upregulation of ELOVL2, plays a critical role in driving enzalutamide resistance in PCa. Functional studies demonstrated that targeted inhibition of ELOVL2 significantly suppressed cancer cell proliferation and restored enzalutamide sensitivity in resistant cells. Mechanistically, ELOVL2 facilitates enzalutamide resistance by impairing the ubiquitin-proteasome system, leading to the subsequent activation of AR signaling pathways.
    Discussion: Our findings demonstrate that ELOVL2 drives enzalutamide resistance in CRPC by stabilizing AR through inhibition of ubiquitin-proteasome-mediated degradation. Targeting ELOVL2 represents a promising therapeutic strategy to overcome resistance in CRPC, with potential to improve clinical outcomes for patients.
    Keywords:  CRPC; ELOVL2; androgen receptor; enzalutamide resistance; prostate cancer
    DOI:  https://doi.org/10.3389/fcell.2025.1598400
  8. ACS Omega. 2025 Jun 17. 10(23): 24601-24617
    Bioinformatics-Driven Engineering of ROS-Responsive Dextran-block-Poly(propylene sulfide) Nanoparticles Functionalized with Folic Acid for Targeted Prostate Cancer Therapy.
    Yixun Zhang, Zhenguo Liang, Zeheng Tan, Jundong Lin, Xinqing Jiang, Xin Zhou, Yangjia Zhuo, Fen Zou, Ronghua Yang, Weide Zhong, Huikang Yang.
      Prostate cancer (PCa) remains a significant challenge in oncology due to its complex pathogenesis and resistance to conventional therapies. By leveraging bioinformatics-guided insights, we identified folate hydrolase 1 (FOLH1) as a crucial biomarker with overexpression in various cancers, particularly PCa. Therefore, we prepared folate receptor-targeted reactive oxygen species (ROS)-responsive dextran-block-poly-(propylene sulfide) nanoparticles to enhance targeted therapeutic efficacy against PCa. The block copolymer was achieved using Cu-(I)-catalyzed "click" chemistry, followed by the successful conjugation of folic acid (FA). Characterization confirmed the nanoparticles' ability to encapsulate doxorubicin (Dox) and respond to ROS, releasing the drug under oxidative conditions. In vitro studies demonstrated enhanced cellular uptake, increased ROS production, and superior cytotoxicity of FA-Dex-b-PPS-Dox in PC3 cells compared to free Dox and nontargeted Dex-b-PPS-Dox nanoparticles. Furthermore, FA-Dex-b-PPS-Dox significantly inhibited tumor cell migration and invasion, emphasizing its potential for comprehensive cancer therapy. In vivo efficacy was assessed using a PC3 tumor model, where FA-Dex-b-PPS-Dox notably reduced tumor volume and weight, with histological analyses confirming enhanced apoptosis and reduced cell proliferation. These findings underscore the promising potential of FA-Dex-b-PPS-Dox in providing a targeted, ROS-responsive therapeutic strategy for prostate cancer.
    DOI:  https://doi.org/10.1021/acsomega.5c01372
  9. J Cell Mol Med. 2025 Jun;29(12): e70669
    Lactylation-Related Gene LILRB4 Predicts the Prognosis and Immunotherapy of Prostate Cancer Based on Machine Learning.
    Qinghua Wang, Xin Qin, Yan Zhao, Wei Jiang, Mingming Xu, Xilei Li, Haopeng Li, Juan Zhou, Gang Wu.
      Lactylation plays a pivotal role in the metabolic reprogramming, proliferation, migration and immune evasion of tumour cells. However, its specific impact on prostate cancer (PCa) remains poorly understood. This study aimed to investigate the role of lactylation related genes (LRGs) in PCa. LRGs were identified and analysed using data from The Cancer Genome Atlas (TCGA), DKFZ2018, GSE46602 and GSE70768 cohorts. Unsupervised clustering was employed to categorise patients with PCa into two distinct clusters. Prognostic models for PCa were developed using multiple machine learning techniques. LRGs signature was established and validated through training and validation sets. The role of leukocyte immunoglobulin-like receptor B4 (LILRB4) in PCa was examined both in vitro and in vivo. Analysis of LRG expression and prognosis in patients with PCa revealed two distinct clusters with differing survival rates and immune responses. Machine learning models demonstrated the ability to predict survival risks, potentially aiding in the development of personalised treatment strategies. Additionally, LILRB4, a key LRG, promotes PCa progression by modulating the NF-κB and PI3K/AKT pathways, highlighting its potential as a therapeutic target. LRGs exert a pivotal influence on PCa, impacting patient prognosis, immune response and drug sensitivity. The LRGs signature emerges as an essential prognostic tool and a promising therapeutic target for PCa.
    Keywords:  LILRB4; lactylation; machine learning; prognosis; prostate cancer
    DOI:  https://doi.org/10.1111/jcmm.70669
  10. Proc Natl Acad Sci U S A. 2025 Jul;122(26): e2502423122
    Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer.
    Nikita Sushentsev, Gregory Hamm, Roido Manavaki, Mary A McLean, Jonathan Birchall, Dmitry Soloviev, David Y Lewis, Luigi Aloj, Lucy Flint, Aleksandr Zakirov, Ian G Mills, Vincent J Gnanapragasam, Anne Y Warren, Simon T Barry, Richard J A Goodwin, Ferdia A Gallagher, Tristan Barrett.
      Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
    Keywords:  MRI; cancer metabolism; nuclear medicine; prostate cancer; spectroscopy
    DOI:  https://doi.org/10.1073/pnas.2502423122
  11. Anticancer Res. 2025 Jul;45(7): 3077-3087
    A Novel Three Small Molecule Inhibitor Combination Therapy For Prostate Cancer.
    Ummuhan Demir, Hilal Badoglu, Irem Nur Cetin, Muhammed Yasar Bener.
       BACKGROUND/AIM: Prostate cancer is common in elderly men. Single treatment options are inadequate for effective therapy. In this study, three small-molecule inhibitors targeting three different pathways related to stemness were combined to obtain an effective antiproliferative effect on prostate cancer cell lines. These small molecules and their corresponding target were: KJ-Pyr-9 as an inhibitor of MYC proto-oncogene bHLH transcription factor (MYC); pyrvinium pamoate as an inhibitor of WNT; and glasdegib as an inhibitor of Sonic Hedgehog (SHH), which induces stem cell properties of cells.
    MATERIALS AND METHODS: Firstly, the half-maximal inhibitory concentration (IC50) and IC25 doses of each drug against the PC-3 cell line and dose optimization for combination of all three drugs were determined. PNT1A cells were used as a healthy control. 3D culture and scratch assays were applied to test efficiency of combined drug treatment.
    RESULTS: According to 2D culture results, the combination was synergistic in PC-3 while its effect was minimal in PNT1A. The combined treatment diminished both viability and size of 3D spheroids of PC-3 and LNCaP cells. In addition, the combined treatment reduced the migratory potential of PC-3 and LNCaP cells.
    CONCLUSION: The combined treatment proposed in this study is novel and promising in overcoming drug resistance and side-effects of single agents and may herald a new era in the treatment paradigm for prostate cancer.
    Keywords:  Combination therapy; KJ-Pyr-9; cancer stem cell properties; glasdegib; pyrvinium pamoate; synergism
    DOI:  https://doi.org/10.21873/anticanres.17672
  12. J Clin Invest. 2025 Jun 24. pii: e180378. [Epub ahead of print]
    BET inhibitors reduce tumor growth in preclinical models of gastrointestinal gene signature-positive castration-resistant prostate cancer.
    Shipra Shukla, Dan Li, Woo Hyun Cho, Dana M Schoeps, Holly M Nguyen, Jennifer L Conner, Marjorie L Roskes, Anisha Tehim, Gabriella Bayshtok, Mohini R Pachai, Juan Yan, Nicholas A Teri, Eric Campeau, Sarah Attwell, Patrick Trojer, Irina Ostrovnaya, Anuradha Gopalan, Ekta Khurana, Eva Corey, Ping Chi, Yu Chen.
      A subgroup (~20-30%) of castration-resistant prostate cancer (CRPC) aberrantly expresses a gastrointestinal (GI) transcriptome governed by two GI-lineage-restricted transcription factors, HNF1A and HNF4G. In this study, we found that expression of GI transcriptome in CRPC correlates with adverse clinical outcomes to androgen receptor signaling inhibitor treatment and shorter overall survival. Bromo- and extra-terminal domain inhibitors (BETi) downregulated HNF1A, HNF4G, and the GI transcriptome in multiple CRPC models, including cell lines, patient-derived organoids, and patient-derived xenografts, while AR and the androgen-dependent transcriptome were largely spared. Accordingly, BETi selectively inhibited growth of GI transcriptome-positive preclinical models of prostate cancer. Mechanistically, BETi inhibited BRD4 binding at enhancers globally, including both AR and HNF4G bound enhancers while gene expression was selectively perturbed. Restoration of HNF4G expression in the presence of BETi rescued target gene expression without rescuing BRD4 binding. This suggests that inhibition of master transcription factors expression underlies the selective transcriptional effects of BETi.
    Keywords:  Cell biology; Drug therapy; Epigenetics; Genetics; Oncology
    DOI:  https://doi.org/10.1172/JCI180378
  13. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00504-0. [Epub ahead of print]
    Isoform-specific function of NSD3 in DNA replication stress confers resistance to PARP inhibitors in prostate cancer.
    Shouhai Zhu, Huanyao Gao, Dan Jiang, Guijie Guo, Jing Hou, Yiqun Han, Chao Zhang, Xiaoping Hu, Shreya Indulkar, Jake A Kloeber, Qi Hu, Yanxia Jiang, Xiangyu Zeng, Yaobin Ouyang, Jing Lu, Ping Yin, Kuntian Luo, Jinzhou Huang, Zheming Wu, Bin Chen, Huaping Xiao, Sonja Dragojevic, Hongran Qin, Xiang Zhou, Jian Jin, Xinyi Tu, Liewei Wang, Zhenkun Lou.
      Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients with deleterious BRCA1/2 alterations. Although this marks a significant milestone, intrinsic or acquired therapy resistance remains a major challenge that limits clinical efficacy. Here, we demonstrate that dysregulated ubiquitination and turnover by the cullin 3 (CUL3)ZBTB2 E3 ligase complex induce the upregulation of the short isoform of nuclear-receptor-binding SET domain protein 3 (NSD3) (NSD3S), which confers PARPi resistance in prostate cancer cells and patient-derived mCRPC samples. Mechanistically, ATR drives the localization of NSD3S at stalled replication forks, where it antagonizes the PTIP-dependent recruitment of the MRE11 nuclease, thereby protecting nascent DNA from extensive degradation and ensuring fork stabilization. Importantly, pharmacological degradation of NSD3S using an NSD3-targeting proteolysis-targeting chimera (PROTAC) efficiently enhances PARPi sensitivity in both cell-line-derived xenograft and patient-derived xenograft (PDX) mouse models. These findings establish NSD3S as a key determinant of PARPi toxicity in mCRPC.
    Keywords:  CUL3; MRE11; NSD3; PARP inhibitor; PTIP; prostate cancer; proteolysis-targeting chimera; replication fork
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.004
  14. Hum Cell. 2025 Jun 23. 38(4): 120
    Identification of autophagy-related biomarkers in prostate cancer prognosis.
    Yancheng Di, Linlin Zhao, Lingling Zhang, Lei Chen.
      Prostate cancer is the second leading cause of cancer-related deaths in males that has an unfavorable outcome. Autophagy-related genes (ARGs) contribute to the process of tumorigenesis and metastasis of prostate cancer. This study aimed to identify ARGs that could serve as reliable and non-invasive biomarkers for evaluating prostate cancer prognosis. The expression profiles of ARGs were identified in prostate cancer specimens with good prognosis (n = 98) and poor prognosis (n = 42). A series of in vitro assays were performed to explore the function and mechanisms of ARGs in malignant progression of prostate cancer. Receiver operating characteristic curve were utilized to evaluate the predictive potential of ARGs for prostate cancer prognosis. Patients with poor prognosis exhibited higher expression of baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) and lower expression of neuregulin 2 (NRG2) compared to those with good prognosis. BIRC5 served as independent risk factors for prostate cancer prognosis, and enhanced BIRC5 expression promoted cells viability, migration, and invasion, but the autophagy activator rapamycin could counteract the effects of the BIRC5 gene. Conversely, NRG2 acted as a protective factor for prostate cancer prognosis, and elevated NRG2 expression suppressed cells viability, migration, and invasion, but the autophagy inhibitor 3-Methyladenine could reverse the effects of the NRG2 gene. The combination of BIRC5, NRG2 with prostate specific antigen (PSA) demonstrated significant predictive value for prostate cancer prognosis. BIRC5 and NRG2 genes participate in the progression of prostate cancer by regulating autophagy. BIRC5 and NRG2 have the potential to serve as valuable biomarkers for the prognosis of prostate cancer.
    Keywords:  Autophagy-related gene; Baculoviral inhibitor of apoptosis repeat containing 5; Biomarker; Neuregulin 2; Prognosis; Prostate cancer
    DOI:  https://doi.org/10.1007/s13577-025-01249-0
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