bims-meproc 2026-03-22 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2026–03–22
fifteen papers selected by
Grigor Varuzhanyan, UCLA

Diminished expression of decorin drives enzalutamide resistance in CRPC by suppressing ACSL4-dependent lipid remodeling and ferroptosis.
Diacylglycerol-Regulated Protein Kinases and Transcriptional Networks in Prostate Cancer.
A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy.
Chromatin regulators TOP2A and PPARGC1A stratify prostate cancer risk and reveal TOP2A-driven progression via PI3K/AKT pathway.
Sphingosine‑1‑phosphate receptor 1 enhances olfactory receptor 51E1‑mediated inhibition of proliferation via Src/JNK signaling in prostate cancer cells.
Mechanism of benzophenone-3 in promoting proliferation and migration of prostate cancer cells via the acyl-CoA dehydrogenase 9 axis.
The dual role of pyroptosis in prostate cancer: new perspectives from molecular mechanisms to clinical translation.
TMPRSS2:ERG-directed radiosensitization: exploiting DNA repair rewiring in gene fusion-positive prostate cancer.
Computational Analysis of Differentially Expressed Circulating MicroRNA and Identification of Key Genes in Prostate Cancer.
Discovery of novel napabucasins bearing sulfonylpiperazine scaffolds as potent STAT3 inhibitors for the treatment of prostate cancer.
Targeting endoplasmic reticulum stress and nitroso-redox imbalance in cancer progression.
Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity.
Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.
Discovery of a Potent RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer.
Exosomal ZFPL1 Identifies Neuroendocrine and Stem Cell-Like Prostate Cancer Subtypes?

Int Immunopharmacol. 2026 Mar 19. pii: S1567-5769(26)00340-1. [Epub ahead of print]177 116496

Diminished expression of decorin drives enzalutamide resistance in CRPC by suppressing ACSL4-dependent lipid remodeling and ferroptosis.

Peng Zhang, Linjie Wu, Jiawei Nie, Zihao Qi, Leijie Wang, Hang Zheng, Zhongqiang Guo, Ying Yu.

  Enzalutamide is a potent androgen receptor (AR) inhibitor widely used for the treatment of castration-resistant prostate cancer (CRPC). However, the development of drug resistance severely limits its therapeutic efficacy, and the underlying mechanisms remain poorly understood. We have demonstrated that decorin (DCN), a suppressor of prostate cancer (PCa) progression, is significantly down-regulated in enzalutamide-resistant PCa cells. Therefore, we hypothesized that diminished expression of DCN contributes to enzalutamide resistance in PCa. In this study, we found that DCN was decreased in enzalutamide-resistant LNCaP cells (LNCaP-ER), which exhibited resistance to ferroptosis. Consistently, DCN was significantly reduced in high-grade PCa and CRPC tissues, as well as in those with poor clinical survival outcomes through integrative analysis. Moreover, DCN overexpression re-sensitized LNCaP-ER cells to enzalutamide by activating ferroptosis. What's more, DCN overexpression significantly inhibited tumor growth and metastasis of LNCaP-ER cells in vivo under enzalutamide-treated conditions, in a ferroptosis-dependent manner. Mechanistically, DCN activated calcium-dependent Protein Kinase C Beta II (PKCβII), thereby enhancing phosphorylation of long-chain acyl-CoA synthetase 4 (ACSL4) to regulate lipid remodeling and promote ferroptosis. In addition, enzalutamide-mediated AR nuclear translocation negatively regulates DCN transcription. In conclusion, promoting DCN-mediated ferroptosis might be a potential strategy for enhancing the sensitivity of enzalutamide in PCa cells. This study delineates a novel mechanism by which DCN downregulation suppresses ferroptosis and drives enzalutamide resistance in CRPC.

Keywords:  CRPC; Decorin; Endocrinotherapy; Enzalutamide; Ferroptosis

DOI:  https://doi.org/10.1016/j.intimp.2026.116496
Endocrinology. 2026 Mar 16. pii: bqag030. [Epub ahead of print]

Diacylglycerol-Regulated Protein Kinases and Transcriptional Networks in Prostate Cancer.

Mariana Cooke, Yousef Elyoussef, Martin C Abba, Marcelo G Kazanietz.

  Effector kinases of the lipid second messenger diacylglycerol (DAG), including protein kinase C (PKC) and protein kinase D (PKD) isozymes, have been widely implicated in the development and progression of prostate cancer. By acting as central hubs of growth factor-mediated signaling, these kinases integrate oncogenic signals with the androgen receptor (AR) pathway, contributing to prostate tumor growth. Distinct members of the DAG-regulated kinases contribute to the acquisition of castration-resistant prostate cancer (CRPC) and bypass AR dependence, promoting the proliferative, migratory, and invasive competencies of androgen-independent prostate cancer cells. As predicted from their coupling to signaling cascades that impact gene expression, PKC/PKD isozymes control the activation of transcription factors such as NF-κB, E2F, and STAT3, and additionally regulate epithelial-to-mesenchymal transition (EMT) transcription factors in prostate cancer cells, providing an additional layer of control in invasive signaling. The aberrant expression/activation of DAG-regulated kinases during prostate cancer progression results in pronounced deregulation and rewiring of transcriptional networks associated with cell cycle control, invasiveness, and cancer cell interactions with the tumor microenvironment (TME). The multifaceted regulation of nuclear functions by these pleiotropic kinases underscores their convoluted roles in prostate cancer development and progression, offering new opportunities for therapeutic targeting.

Keywords:  PKC; PKD; gene expression; prostate cancer; signal transduction; transcriptional networks

DOI:  https://doi.org/10.1210/endocr/bqag030
Cell Death Dis. 2026 Mar 19.

A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy.

Jia-Yin Chen, Yu-Ting Xue, Bin Lin, Xu-Yun Huang, Fei Lin, Dong-Ning Chen, Wan-Jin Zhang, Yong Wei, Xue-Yi Xue, Qing-Shui Zheng, Zhi-Bin Ke, Ning Xu.

The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.

DOI: https://doi.org/10.1038/s41419-026-08577-5
Chin J Cancer Res. 2026 Feb 28. 38(1): 83-99

Chromatin regulators TOP2A and PPARGC1A stratify prostate cancer risk and reveal TOP2A-driven progression via PI3K/AKT pathway.

Zhipeng Wang, Jie Wang, Shuang Chen, Ruicheng Wu, Zhouting Tuo, Luxia Ye, Koo Han Yoo, Dengxiong Li, Xiaodong Jin, Wei Xiong, Dechao Feng.

   Objective: To identify chromatin regulators (CRs)-based molecular subtypes and risk scores for accurately predicting biochemical recurrence (BCR) after radical prostatectomy (RAP) in prostate cancer (PCa) patients.
Methods: Differentially expressed genes (DEGs) between tumor and normal samples from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) databases were intersected with CR-related and prognostic genes. Consensus clustering, risk score analysis, functional analysis, immune microenvironment, m6A, and heterogeneity assessments were performed using R software. In vitro validation used DU145 and C42B PCa cell lines. Topoisomerase II alpha (TOP2A) was knocked down via siRNA. Assays included CCK-8 proliferation, colony formation, transwell migration/invasion, wound healing, and western blotting (WB) for pathway validation.
Results: TOP2A and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) defined molecular subtypes and a risk score in TCGA, validated in a GEO dataset. Cluster 2 exhibited significantly shorter BCR-free survival vs. cluster 1 in TCGA [hazard ratio (HR): 2.21; 95% confidence interval (95% CI): 1.32-3.73; P=0.003)], GEO (HR: 2.05; 95% CI: 1.05-4.02; P=0.010), and MSKCC2010 (HR: 5.93; 95% CI: 1.96-17.87; P<0.001). Similar survival differences were observed between high- and low-risk groups (defined by the median risk score). Cluster 2 showed greater tumor heterogeneity and higher m6A gene expression. Gene set variation analysis (GSVA) revealed downregulated cell-cycle pathways in cluster 2, alongside suppressed tumor-infiltrating immune cells. TOP2A knockdown significantly impaired PCa cell proliferation, colony formation, migration, and invasion. Mechanistically, it suppressed phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) pathway activation, reducing phosphorylated PI3K and AKT levels without altering total protein.
Conclusions: TOP2A and PPARGC1A effectively stratify PCa subtypes for RAP patients. TOP2A drives malignant progression via the PI3K/AKT pathway.

Keywords:  PI3K/AKT pathway; Prostate cancer; biochemical recurrence; chromatin regulator; molecular subtypes

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2026.01.06
Oncol Rep. 2026 May;pii: 98. [Epub ahead of print]55(5):

Sphingosine‑1‑phosphate receptor 1 enhances olfactory receptor 51E1‑mediated inhibition of proliferation via Src/JNK signaling in prostate cancer cells.

Kiheon Kim, Jinwoo Lee, Chulwon Choi, Jungnam Bae, Hee-Jung Choi, Won-Ki Huh.

  Olfactory receptors (ORs) are ectopically expressed in multiple cancers and can regulate tumor cell behavior, yet their clinical relevance and regulatory mechanisms remain poorly defined. OR51E1 is highly expressed in prostate cancer (PC) and suppresses tumor cell proliferation upon activation, but its expression alone does not correlate with patient prognosis, suggesting additional regulatory factors. Using transcriptomic analyses of The Cancer Genome Atlas and Genotype‑Tissue Expression datasets, functional screening of G‑protein‑coupled receptors, and mechanistic studies in PC cells, sphingosine‑1‑phosphate receptor 1 (S1PR1) was identified as a key modulator of OR51E1 function. Activation of OR51E1 by nonanoic acid (NA) or butyric acid reduced PC cell survival in an OR51E1‑dependent manner, and this effect was abolished in OR51E1 knockout cells. S1PR1 enhanced OR51E1‑mediated signaling by increasing its surface expression and amplifying downstream apoptotic responses. Although OR51E1 activation induced cAMP signaling, NA‑induced cytotoxicity was independent of the canonical Gs/olf‑cAMP pathway and instead required Src and JNK activation, which was further potentiated by S1PR1. Clinically, co‑expression of OR51E1 and S1PR1 was significantly associated with improved progression‑free interval in patients with prostate adenocarcinoma, particularly in stage II disease, whereas OR51E1 expression alone showed no prognostic value. Collectively, these findings define a previously unrecognized OR51E1‑S1PR1 signaling axis that suppresses PC cell survival through Src/JNK‑dependent mechanisms and highlight GPCR‑mediated regulation of ectopic olfactory receptors as a determinant of tumor behavior and patient outcome.

Keywords:  JNK pathway; OR51E1; S1PR1; apoptosis; prostate cancer; tumor suppression

DOI:  https://doi.org/10.3892/or.2026.9103
Ecotoxicol Environ Saf. 2026 Mar 19. pii: S0147-6513(26)00335-0. [Epub ahead of print]314 120006

Mechanism of benzophenone-3 in promoting proliferation and migration of prostate cancer cells via the acyl-CoA dehydrogenase 9 axis.

Jinhui Jian, Jiongxuan Xu, Guilin Wang, Xingmo Dong, Jian Lin, Yuanfu Zhong, Lihe Xie, Shangyuan Xu, Xiaoshuai Li, Dewen Zhong.

  Prostate cancer (PCa) remains one of the most common malignancies in men, with rising global incidence and mortality rates. Recently, the impact of environmental pollutants on PCa initiation and progression has garnered significant attention. Benzophenone-3 (BP3), a ubiquitous ultraviolet filter in personal care products, possesses potential endocrine-disrupting and pro-carcinogenic properties; however, its specific role in PCa remains poorly defined. In this study, we demonstrated that BP3 significantly promoted PCa cell proliferation and migration. A BP3-derived nomogram was developed, which not only predicted PCa prognosis but also revealed an associated immunosuppressive microenvironment characterized by increased Treg and M2 macrophage infiltration alongside decreased CD8⁺ T cell populations. Mechanistic investigations identified acyl-CoA dehydrogenase 9 (ACAD9) as a pivotal mediator of these effects, as ACAD9 knockdown effectively reversed BP3-induced oncogenic phenotypes. Functional assays further elucidated that BP3 accelerates the fatty acid oxidation (FAO) rate while suppressing reactive oxygen species (ROS) production, a metabolic shift abrogated by ACAD9 silencing. Finally, in vivo xenograft models validated that BP3 monotherapy markedly promotes PCa progression, whereas ACAD9 deficiency neutralizes this effect. In summary, our findings characterized BP3 as an environmental pro-carcinogen that drives PCa malignancy via the BP3/ACAD9 axis, offering new insights into environmental risk factors and potential therapeutic targets for PCa.

Keywords:  ACAD9; Benzophenone-3; Migration; Proliferation; Prostate cancer

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120006
Mol Biol Rep. 2026 Mar 16. pii: 496. [Epub ahead of print]53(1):

The dual role of pyroptosis in prostate cancer: new perspectives from molecular mechanisms to clinical translation.

Wenjian Li.



Keywords:  Combination therapy; Gasdermin protein; Prostate cancer; Pyroptosis; Therapeutic resistance

DOI:  https://doi.org/10.1007/s11033-026-11681-6
J Clin Invest. 2026 Mar 16. pii: e203657. [Epub ahead of print]136(6):

TMPRSS2:ERG-directed radiosensitization: exploiting DNA repair rewiring in gene fusion-positive prostate cancer.

Xiaoju Wang, Arul M Chinnaiyan.

The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpression in human prostate cancer cells rewired DNA double-strand break repair toward a poly(ADP-ribose) polymerase 1-dependent (PARP1-dependent) alternative end-joining pathway without disrupting canonical repair. This repair bias created a conditional dependency on PARP1 that was exposed by radiotherapy, rendering ERG-positive tumors selectively sensitive to PARP inhibition-mediated radiosensitization. The tumor-selective cytotoxic effect of combined PARP1 inhibition and irradiation was corroborated in human-derived prostate cancer organoids. These findings establish ERG as a predictive biomarker for precision radiotherapy and highlight a tumor-selective strategy to enhance radiotherapeutic efficacy in prostate cancer.

DOI: https://doi.org/10.1172/JCI203657
Indian J Clin Biochem. 2026 Apr;41(2): 243-250

Computational Analysis of Differentially Expressed Circulating MicroRNA and Identification of Key Genes in Prostate Cancer.

Anveshika Manoj, Shweta Kumari, Gautam Prasad, Mohammad Kaleem Ahmad.

  Bioinformatics is considered a powerful tool to investigate and deeply analyze large datasets. A significant quantity of data is generated by prostate cancer and dysregulation of microRNA (miRNA) in tissues and bodily fluids (serum, plasma, urine). Screening dysregulated miRNA is currently more accessible, more reliable, and more precise with the help of insilico approaches. Hence the objective of the study is to identify miRNAs and explore their mRNA interaction in prostate cancer development. Here in the present study, we analyzed the GEO dataset GSE112264 and performed GEO-2R analysis to segregate significantly upregulated and downregulated miRNAs. The targetome of each miRNA containing several target genes was analyzed and put in an interactive network form. Functional enrichment analysis using DAVID 6.8 and GSEA was carried out to get KEGG, Reactome, and GO-BP analysis. Our analysis revealed that out of 190 overlapped significant miRNAs, only 9 miRNAs (hsa-miRNA-185-5p, hsa-miRNA-211-5p, hsa-miRNA-330-3p, hsa-miRNA-342-3p, hsa-miRNA-3622b-5p, hsa-miRNA-486-5p, hsa-miRNA-520a-3p, hsa-miRNA-550a-3p, hsa-miRNA-574-3p) were found to target 20 unique target genes (AKT1, EP300, E2F1, KRAS, AR, CREB5, CCND1, CDKNA1, EGFR, ERBB2, FGFR1, FOXO1, IKBKG, IGF1R, MAPK1, PTEN, PIK3R1, and TP53) that were involved in Prostate cancer survival and proliferation. Out of 9 miRNAs, two miRNAs (miRNA-520a-3p and miRNA-550a-3p) are novel miRNAs that have yet to be explored in Prostate cancer pathogenesis. To conclude and for future research, 8 miRNAs are yet to be explored for non-invasive potential as diagnostic and prognostic biomarkers in Prostate cancer progression and development. The target genes of each miRNA could provide novel insights in developing therapeutics for better management of disease.

Keywords:  Bioinformatics analysis; Circulating microRNA; GEO dataset; Gene enrichment; Prostate cancer; Target genes

DOI:  https://doi.org/10.1007/s12291-024-01237-5
Eur J Med Chem. 2026 Mar 12. pii: S0223-5234(26)00219-9. [Epub ahead of print]309 118774

Discovery of novel napabucasins bearing sulfonylpiperazine scaffolds as potent STAT3 inhibitors for the treatment of prostate cancer.

Chong Zhang, Limin Yang, Song Li, Dingke Ma, Yan Qu, Liqiang Wu.

  Prostate cancer (PCa) is a frequently observed male cancer characterized by high morbidity and mortality. STAT3 is closely related to the occurrence and development of cancer, suggesting that it may be an antitumor therapeutic target. In this study, we prepared various napabucasins bearing sulfonylpiperazine scaffolds as STAT3 inhibitors to treat PCa. Among these compounds, YN11 was the most potent, with an IC50 value of 23 nM in DU145 cells, which is 8.8 times greater than the IC50 value of napabucasin. Mechanistic studies revealed that YN11 directly binds to the STAT3 SH2 domain, inhibiting the phosphorylation of STAT3 while reducing the expression of downstream target proteins. Moreover, YN11 triggered cell cycle arrest, promoted apoptosis, and effectively suppressed PCa cell invasion and migration. In vivo studies revealed that YN11 significantly inhibited tumor growth without inducing considerable weight loss or apparent histopathological alterations in major organs. Our findings indicate that YN11 is a potent STAT3 inhibitor for treating PCa.

Keywords:  Antitumor; Napabucasin; Prostate cancer; STAT3

DOI:  https://doi.org/10.1016/j.ejmech.2026.118774
Trends Mol Med. 2026 Mar 19. pii: S1471-4914(26)00037-7. [Epub ahead of print]

Targeting endoplasmic reticulum stress and nitroso-redox imbalance in cancer progression.

Himanshu Arora, Rehana Qureshi.

  Therapy-resistant cancers exploit cellular stress programs to survive. Evidence from neuroendocrine prostate cancer reveals that the loss of nitric oxide-dependent redox signaling amplifies endoplasmic reticulum stress and lineage plasticity. Restoring physiological nitroso-redox balance may reprogram stress adaptation and expose new vulnerabilities in aggressive cancers.

Keywords:  MYCN; S-nitrosylation; endoplasmic reticulum stress; lineage plasticity; neuroendocrine prostate cancer; nitric oxide

DOI:  https://doi.org/10.1016/j.molmed.2026.02.007
J Clin Invest. 2026 Mar 17. pii: e200260. [Epub ahead of print]

Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity.

Yatian Yang, Xiong Zhang, Varadha Balaji Venkadakrishnan, Hongye Zou, Xingling Zheng, Shiyao Guo, Christopher Z Chen, Alexander D Borowsky, Eva Corey, Ronald M Evans, Allen C Gao, Marc A Dall'Era, Amina Zoubeidi, Primo N Lara, Hsing-Jien Kung, Xinbin Chen, Himisha Beltran, Hong-Wu Chen.

  PRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for treatment of advanced cancers including metastatic prostate cancer. Here we show that PRC2i/EZH2i alone or in combination with AR inhibitors induce diverse cell state programs (CSP) (e.g., response to stress or interferon, MYC targets, stem cell, EMT and multiple developmental programs) which led to increased tumor cell invasion, metastasis and resistance to other drugs, in addition to modest suppression of tumor growth. In contrast to the current perception, our comprehensive, integrated genomics and epigenomics profiling of PDX and clinical tumors revealed that PRC2/EZH2 suppresses CSP genes through maintaining chromatin bivalency. Hyperactive Wnt/β-catenin signaling and inhibitors of PRC2/EZH2 and AR alter chromatin bivalency through antagonizing PRC2 and stimulating MLL2/KMT2B in a feedforward manner. Circadian rhythm regulator REV-ERBα unexpectedly reprograms β-catenin in promoting bivalency resolution and CSP gene expression. Dual targeting of Wnt/β-catenin and EZH2 diminishes diverse cell states through restoring bivalency and effectively block tumor growth. Our findings provide unexpected insights of chromatin bivalency and dysregulated circadian rhythm in control of cell state diversity and offer alternative therapeutic strategies targeting PRC2/EZH2 for advanced malignancies.

Keywords:  Cell biology; Epigenetics; Genetics; Molecular biology; Oncology; Prostate cancer

DOI:  https://doi.org/10.1172/JCI200260
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2532814123

Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.

Evan R Abt, Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M Peña-Garcia, Lauryn Ruegg, Jami McLaughlin, Donghui Cheng, Nikolas G Balanis, Chia-Chun Chen, Yang Xu, Yi Xing, Sanaz Memarzadeh, Caius G Radu, Thomas G Graeber, Owen N Witte.

  Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.

Keywords:  RB tumor suppressor; nucleotide metabolism; small cell cancer; synthetic lethality

DOI:  https://doi.org/10.1073/pnas.2532814123
J Med Chem. 2026 Mar 20.

Discovery of a Potent RXRγ Degrader WCF-598 for the Treatment of Castration-Resistant Prostate Cancer.

Chaofan Wang, Jieying Lin, Junping Pei, Zhanfang Kang, Zhuoheng Liu, Junwei Li, Guodi Cai, Yang Zhou, Junjian Wang, Hong Wang, Xiaoyun Lu.

Castration-resistant prostate cancer (CRPC) remains a significant therapeutic challenge with limited effective treatment options. We identified retinoid X receptor γ (RXRγ) as a critical regulator of CRPC cell proliferation, highlighting it as a previously unrecognized and tractable target for therapeutic intervention. However, no RXRγ-selective modulators have been reported. Herein, we utilized the PROTAC approach to develop WCF-598 as a potent RXRγ degrader, which exhibits preferential degradation of RXRγ over RXRα and RXRβ isoforms. WCF-598 promoted efficient RXRγ degradation through the ubiquitin-proteasome system, leading to robust antiproliferative activity in CRPC models. In vivo, WCF-598 induced significant tumor regression in 22Rv1 xenograft-bearing mice without observable toxicity. Notably, WCF-598 also exhibited a secondary activity by degrading androgen receptor splice variant 7 (AR-V7), a clinically relevant driver of therapy resistance in CRPC. These results establish WCF-598 as a specific chemical probe for investigating the function of RXRγ in CRPC and potentially other RXRγ-related diseases.

DOI: https://doi.org/10.1021/acs.jmedchem.5c03442
Prostate. 2026 Mar 15.

Exosomal ZFPL1 Identifies Neuroendocrine and Stem Cell-Like Prostate Cancer Subtypes?

Neshat Masud, Johnmesha Sanders, Kenneth A Iczkowski, Girish V Shah.

   BACKGROUND: Calcitonin (CT) and its receptor promote prostate cancer (PC) progression and metastasis. Identifying downstream CT-regulated genes may provide clinically useful biomarkers.
METHODS: Subtraction hybridization was used to identify CT-inducible genes. Expression of zinc finger protein-like 1 (ZFPL1) was examined in malignant versus benign prostate tissues and evaluated for regulation by CT and androgens. Exosomal secretion of ZFPL1 protein was assessed, and plasma levels were measured in PC patients compared with cancer-free individuals. Immunohistochemistry was performed to assess ZFPL1 localization with neuroendocrine (NE) and stem cell markers.
RESULTS: ZFPL1 was strongly expressed in malignant prostates but nearly absent in benign tissues. Its expression was upregulated by both CT and androgens. ZFPL1 protein was secreted through exosomes, and plasma concentrations in PC patients were at least fourfold higher than in cancer-free controls. Immunohistochemistry confirmed ZFPL1 co-localization with NE and stem cell markers, suggesting an association with aggressive, androgen-resistant PC.
CONCLUSIONS: ZFPL1 is a CT- and androgen-regulated protein selectively expressed in malignant prostate cells and secreted via exosomes. Its elevated plasma levels and association with aggressive disease highlight its promise as a non-invasive biomarker for PC detection and monitoring.

Keywords:  calcitonin; cancer marker; neuroendocrine; prostate cancer; zinc finger protein like 1

DOI:  https://doi.org/10.1002/pros.70148