bims-meproc 2025-08-17 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–08–17
eight papers selected by
Grigor Varuzhanyan, UCLA

Resilience and vulnerabilities of tumor cells under purine shortage stress.
The RNA helicase DDX17 enhances androgen receptor stability by interacting with the E3 ubiquitin ligase SPOP in prostate cancer.
SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer.
The status of p53 affects the efficacy of PLK1 inhibitor BI6727 in prostate cancer cells.
Polystyrene microspheres could inhibit the ferroptosis of prostate cancer cells via USP39/IGF2BP3/MAPK4 axis.
Anti-tumor activity of CDYL2b in prostate cancer.
Synergistic anticancer effect of CDRI-08 and abiraterone acetate against castration resistant prostate cancer targeting PI3K/Akt pathway.
[Mechanism of icariin inhibiting the proliferation of human prostate cancer PC-3 cells: An exploration based on cell metabolomics].

Clin Cancer Res. 2025 Aug 11.

Resilience and vulnerabilities of tumor cells under purine shortage stress.

Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.

PURPOSE: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.
EXPERIMENTAL DESIGN: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.
RESULTS: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity.
CONCLUSIONS: Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1667
Transl Androl Urol. 2025 Jul 30. 14(7): 1978-1989

The RNA helicase DDX17 enhances androgen receptor stability by interacting with the E3 ubiquitin ligase SPOP in prostate cancer.

Maierhaba Maheremu, Bowen Zheng, Haoran Wen, Qiang Wei, Shidong Lv.

   Background: Prostate cancer (PCa) is a common malignancy in men, closely associated with androgen receptor (AR) signaling, and often diagnosed with elevated prostate-specific antigen (PSA). While androgen deprivation therapy (ADT) is effective, resistance develops due to reactivation of AR signaling, driving disease progression. We aimed to explore the role of DDX17 in the progression of PCa through its interaction with SPOP. We hypothesized that DDX17 can stabilize the AR by inhibiting SPOP-mediated ubiquitination, thereby maintaining AR signaling which supports tumor growth and survival.
Methods: We collected gene expression data and clinical information from PCa patients from The Cancer Genome Atlas and Gene Expression Omnibus databases. Messenger RNA (mRNA) and protein levels were quantified using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell viability and invasion capabilities were assessed using cell counting kit-8 (CCK-8) and transwell invasion assays. The interactions between DDX17 and SPOP were examined through coimmunoprecipitation assays.
Results: DDX17 exhibited high expression in both PCa tissues and cells. Silencing DDX17 led to reduced proliferation and invasion of PCa cells. Mechanistic investigations revealed that DDX17 directly interacted with SPOP, sustaining AR stability by preventing AR ubiquitination. These findings suggest a role of DDX17 in promoting the progression of PCa by binding and blocking SPOP ubiquitination of AR.
Conclusions: This study elucidated a novel mechanism through which the RNA helicase DDX17 can promote PCa progression through its interaction with SPOP, thereby enhancing AR stability by inhibiting AR ubiquitination.

Keywords:  DDX17; Prostate cancer (PCa); SPOP; androgen receptor (AR); ubiquitination

DOI:  https://doi.org/10.21037/tau-2025-167
bioRxiv. 2025 Jul 19. pii: 2025.07.18.664790. [Epub ahead of print]

SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer.

John T Phoenix, Audris Budreika, Devin A Schmeck, Raymond J Kostlan, Marina G Ferrari, Kristen S Young, Charles S Rogers, Carleen D Deegan, Marcus W Bienko, Hannah E Bergom, Ella Boytim, Ryan M Brown, Julia A Walewicz, Shreya K Bhagi, Leigh Ellis, Emmanuel S Antonarakis, Justin M Drake, Pushpinder S Bawa, Jordan E Vellky, Anthony Williams, Natalie M Rezine, Jonathan P Rennhack, Sean W Fanning, Justin H Hwang, Russell Z Szmulewitz, Donald J Vander Griend, Steven Kregel.

Treatment options and diagnostic outlook for men with advanced, therapy resistant prostate cancer (PCa) are extremely poor; this is primarily due to the common lack of durable response to androgen receptor (AR) targeted therapies and phenotypic transdifferentiation into a particularly lethal subtype known as neuroendocrine prostate cancer (NEPC). In this study, we mechanistically determine that SOX2 (a transcription factor originally repressed by AR) physically binds and acts in a concerted manner with FOXA1 (a key AR pioneering cofactor) to regulate a subset of genes which promote cell cycle progression, and lineage plasticity in AR-refractory prostate cancers. Our findings assert the SOX2/FOXA1 interaction as an important mediator of resistance to AR-targeted therapy and a driver of NEPC and lineage plasticity; their coordinated action and downstream signaling offers a potential novel therapeutic opportunity in late-stage PCa.

DOI: https://doi.org/10.1101/2025.07.18.664790
Front Cell Dev Biol. 2025 ;13 1602693

The status of p53 affects the efficacy of PLK1 inhibitor BI6727 in prostate cancer cells.

Wenjing Li, Ying Wang, Wenzheng Guo, Donghua Wen.

  As there are no effective treatments for advanced prostate cancer, exploring new therapies is crucial. BI6727(Volasertib), a PLK1 inhibitor, shows great promise as an anti-cancer drug. However, despite advancing to phase II and III trials in other cancers, BI6727 has shown limited anti-tumor activity in prostate cancer, making it crucial to investigate the underlying reasons for this discrepancy. In this study, we found that the status of p53 affects the sensitivity of prostate cancer cells to BI6727. Prostate cancer cells PC3 (long-term loss of p53 expression), DU145 (expressing mutant-type p53) and LNCaP (expressing wild-type p53) were treated with BI6727, respectively. It was found that PC3 cells were more sensitive to BI6727 when wild-type p53 was introduced into these cancer cells; while apoptosis induced by BI6727 was reduced after knockdown of p53 in LNCaP cells. In additional, in DU145 cells, the presence of points mutation in p53 exerted a dominant negative effect, attenuating BI6727-induced apoptosis. Further analysis revealed that missense mutations in the P53 gene are widespread in prostate cancer patients. Mechanistically, BI6727 reduces the degradation of Topors, thereby increasing the stability of p53 by reducing its ubiquitination. This ultimately influences the sensitivity of prostate cancer cells with different p53 statuses to BI6727.In summary, this study identifies p53 as a key factor limiting the clinical efficacy of BI6727 in prostate cancer cells.

Keywords:  BI6727; PLK1; PLK1 inhibitor; p53; prostate cancer

DOI:  https://doi.org/10.3389/fcell.2025.1602693
J Transl Med. 2025 Aug 11. 23(1): 891

Polystyrene microspheres could inhibit the ferroptosis of prostate cancer cells via USP39/IGF2BP3/MAPK4 axis.

Shengming Lu, Ruipeng Wu, Weijian Li, Zhenyu Fu, Xuefei Ding, Yang Luan, Huang Tianbao, Yuhua Huang.

   BACKGROUND: Polystyrene (PS) particles, which have been recognized as emerging environmental pollutants, have increasingly been associated with various human diseases. However, their specific role and underlying mechanisms in prostate cancer development have not been fully elucidated.
METHODS: We investigated the characterization properties of PS particles. Subsequently, we examined the impact of PS particles on prostate cancer proliferation using in vitro experiments. Through mRNA sequencing, RIP, and mass spectrometry analysis, we confirmed a close interaction among USP39, IGF2BP3, and MAPK4. The rescue experiment demonstrated that ferroptosis is intricately involved in this process. To further validate our results, we performed mouse xenograft experiments.
RESULTS: In this study, PS particles significantly enhanced the proliferation, migration, and invasion of prostate cancer cells through the regulation of ferroptosis. It was found that USP39 interacts with IGF2BP3, which, in turn, stabilizes MAPK4, a key regulator of ferroptosis.
CONCLUSIONS: These findings illuminate the complex relationship between environmental pollutants such as PS and cancer progression, offering new avenues for research and potential therapeutic interventions in prostate cancer.

Keywords:  Ferroptosis; Prostate cancer; Ubiquitination

DOI:  https://doi.org/10.1186/s12967-025-06868-7
Cancer Lett. 2025 Aug 12. pii: S0304-3835(25)00557-9. [Epub ahead of print]632 217987

Anti-tumor activity of CDYL2b in prostate cancer.

Ruicai Gu, Julia Janknecht, Sangphil Oh, Hanlin Jiang, Ralf Janknecht.

  Prostate cancer is a leading cause of death among men, yet the molecular underpinnings of this malignancy are still not fully understood. We discovered that two histone demethylases driving prostate tumorigenesis, the JMJD2A and JMJD2B enzymes, suppressed transcription of the CDYL2 epigenetic reader gene. Bioinformatic analyses showed that low CDYL2 expression in prostate tumors was associated with more metastasis and disease recurrence as well as reduced survival. Out of the four predicted CDYL2 isoforms, all of which were capable of forming homo- and heteromers, only CDYL2b was appreciably expressed in prostate cancer cells and tightly associated with chromatin. Overexpression of CDYL2b in human DU145 and 22Rv1 prostate cancer cells decreased their growth and clonogenic activity in vitro as well as tumor expansion in nude mice, while CDYL2b downregulation stimulated LNCaP cell growth. RNA sequencing exposed that CDYL2b induced upregulation of transcription factor genes HES7, KLF17 and TBX6 and overexpression of those factors phenocopied to various degrees the anti-oncogenic effects of CDYL2b. Further JMJD2B, but not JMJD2A, robustly formed complexes with CDYL2b and antagonized CDYL2b in upregulating HES7 transcription. In conclusion, our data highlight that CDYL2b can suppress prostate tumorigenesis, while JMJD2A and JMJD2B may exert their pro-oncogenic functions in part through stifling CDYL2b transcription or CDYL2b activity. In addition, our study revealed that the developmental transcription factors TBX6 and HES7 may also suppress tumorigenesis.

Keywords:  CDYL2; Epigenetics; JMJD enzyme; Prostate cancer; Transcription

DOI:  https://doi.org/10.1016/j.canlet.2025.217987
Iran J Basic Med Sci. 2025 ;28(9): 1163-1170

Synergistic anticancer effect of CDRI-08 and abiraterone acetate against castration resistant prostate cancer targeting PI3K/Akt pathway.

Bhavana Jonnalagadda, Sumathy Arockiasamy.

   Objectives: There is a considerable interest in combination therapy targeting the complex interlinked pathways in prostate cancer due to the development of drug resistance with monotherapies. A standardized fraction of Bacopa monnieri CDRI-08 was developed and patented by the Central Drug Research Institute (CDRI), Lucknow, for the treatment of neurodegenerative diseases. Recent studies with the plant and its phytocompounds have shown effective anticancer and antioxidant activity. Therefore, in the current research, the combined effect of Abiraterone acetate (AA) and CDRI-08 was studied in androgen-independent prostate cancer cells in vitro.
Materials and Methods: Initially, the in vivo toxicity of CDRI-08 was studied in zebrafish embryos. In vitro individual cytotoxicity and the synergistic effect of AA and CDRI-08 were studied in PC3 cell lines with and without growth factors. Nuclear staining with AO/EB and western blotting were performed to analyse apoptotic cell death and changes in protein expression of p-AKT and Casp3 in individual and combination-treated cells.
Results: CDRI-08 has shown no toxicity and teratogenicity in zebrafish embryos. AA and CDRI-08 have shown dose-dependent cytotoxic effects in PC3 cell lines with and without growth factors. Synergism was observed with different concentration ratios of AA and CDRI-08 with and without growth factors, with a good combination index (CI). Apoptosis was observed in individual and combination treated cells with an increase in Casp3 and simultaneous decrease in p-AKT expression levels.
Conclusion: The study confirms the synergistic effect of CDRI-08 and AA at a lower dose, targeting the tyrosine kinase and androgen receptor pathways.

Keywords:  Abiraterone; CDRI-08; Combination index; PI3K/Akt pathway; Prostate cancer

DOI:  https://doi.org/10.22038/ijbms.2025.85330.18441
Zhonghua Nan Ke Xue. 2024 Nov;30(11): 963-973

[Mechanism of icariin inhibiting the proliferation of human prostate cancer PC-3 cells: An exploration based on cell metabolomics].

Tao Wang, Wei Wang, Wen-Jun Xiong, Zi-Jing Zhang, Fei Wang, Yao-Hui Peng, Yan Chen, Hai-Ping Zeng, Li-Jie Luo.

OBJECTIVE: To study the mechanism of icariin inhibiting the proliferation of human PCa PC-3 cells based on cell metabolomics technology.
METHODS: We determined the proliferation activity of human PC-3 cells by methyl thiazolyl tetrazolium(MTT) assay, and compared the proliferation of the PC-3 cells among the control, 5-fluorouracil and icariin intervention groups. Using the Bligh Dyer method, we extracted endogenous metabolites from the cells, analyzed the metabolic profile by ultra-high pressure liquid chromatography tandem quadrupole time-of-flight mass spectrometry, identified the differential metabolites by principal component analysis and orthogonal partial least-squares discrimination analysis, and enriched the metabolic pathways based on the MetaboAnalyst database.
RESULTS: Icariin significantly inhibited the proliferation of human PCa PC-3 cells. A total of 89 differential metabolites were identified, mainly including amino acids, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, and lysophosphatidylethanolamine, all with the tendency to return to the normal level after icariin intervention. Icariin significantly downregulated the metabolic levels of the glycerophospholipid metabolites phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylethanolamine, and upregulated those of amino acid metabolites tryptophan, leucine, and proline in the PC-3 cells.
CONCLUSION: Icariin inhibits the proliferation of human PCa PC-3 cells, which may be closely related to its regulatory effect on lipid metabolism (glycerophospholipid metabolism) and amino acid metabolism.

Keywords: icariin; PC-3 cell; glycerophospholipid metabolism; amino acid metabolism; cell metabolomics