bims-meproc 2025-08-10 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–08–10
eighteen papers selected by
Grigor Varuzhanyan, UCLA

Targeted Metabolic Alterations in Prostate Cancer: A Promising Therapeutic Strategy.
Proteomic profiling of extracellular vesicles distinguishes prostate cancer molecular subtypes.
Caloric Restriction Enhances the Efficacy of Anti-Androgen Therapy in Prostate Cancer by Inhibiting Androgen Receptor Translation.
AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.
Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion.
Transcriptomic and functional analysis of triphenyl phosphate exposure in prostate cancer progression.
Tumor Cholesterol Synthesis, Statin Use, and Lethal Prostate Cancer.
SLC7A11 upregulation via AR and NEDD4L ubiquitination contributes to ferroptosis inhibition and enzalutamide resistance in castration-resistant prostate cancer.
Integrative genomic analysis identifies DPP4 inhibition as a modulator of FGF17 and PDGFRA downregulation and PI3K/Akt pathway suppression leading to apoptosis.
The impact of dexamethasone on cellular stress responses caused by mild serum deprivation in androgen-insensitive prostate cancer cells.
Integrated Omics and Multi-Cohort Analyses Identify an Enhancer Variant Linking Ferroptosis to Precision Therapy in Prostate Cancer.
Nitric Oxide Tuning Enhances Cytotoxicity and Reduces Inflammation in Prostate Cancer Nanotherapy.
Advances in targeted therapies by PARP inhibitors for the treatment of prostate cancer: A scientometric approach.
PKA-driven SPP1 activation as a novel mechanism connecting the bone microenvironment to prostate cancer progression.
Integrated Transcriptomic and Metabolomic Analyses in Characterizing the Anti-Prostate Cancer Effects of Hederagenin.
The kinesin-14 family motor protein KIFC2 promotes prostate cancer progression by regulating p65.
SREBF1-mediated SND1 transcriptional activation promotes prostate cancer progression via MTDH interaction through the SESN2/AMPK/mTOR axis.
Cuproptosis in prostate cancer: Molecular mechanisms, prognostic biomarkers and therapeutic frontiers of cuproptosis‑related genes (Review).

Mol Pharm. 2025 Aug 04.

Targeted Metabolic Alterations in Prostate Cancer: A Promising Therapeutic Strategy.

Zhanning Qu, Feng Hao, Zhaojun Li, Liu Yang, Hongxia Gao, Junying Li, Shuang Chen, Liguo Wang, Zhiming Xiu, Cheng Hu.

  The treatment of prostate cancer (PCa) remains a major challenge due to the development of resistance to androgen receptor (AR)-targeted therapies and paclitaxel-based chemotherapeutic agents, highlighting the need for novel therapeutic approaches. Unlike the majority of tumor cells that depend on aerobic glycolysis (the Warburg effect) for energy production, early stage PCa primarily utilizes oxidative phosphorylation (OXPHOS), while advanced-stage PCa shifts to aerobic glycolysis. Consequently, targeting metabolic alterations specific to PCa may represent a promising therapeutic strategy. This review initially delineates the glucose metabolism phenotype characteristic of healthy prostate cells as well as primary and metastatic PCa cells, which underpin the development and progression of the disease. Subsequently, it elaborates on the roles and mechanisms of inhibitors targeting key enzymes involved in glycolysis and the synthesis of OXPHOS in the context of PCa treatment. Finally, the review discusses inhibitors that concurrently target both glycolysis and OXPHOS, potentially mitigating the compensatory pathways that support cancer cell survival. Collectively, this review contributes to a deeper understanding of metabolic alterations in PCa and informs the ongoing development of therapeutic interventions.

Keywords:  glycolysis; metabolic alteration; oxidative phosphorylation; prostate cancer; target therapy

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00341
bioRxiv. 2025 Aug 02. pii: 2025.07.31.667906. [Epub ahead of print]

Proteomic profiling of extracellular vesicles distinguishes prostate cancer molecular subtypes.

Megan L Ludwig, Ali T Arafa, Saasha Vinoo, Jason C Jones, Abderrahman Day, Hannah E Bergom, Zoi Sychev, Alec Horrmann, Nicholas M Levinson, Scott M Dehm, Emmanuel S Antonarakis, Justin Hwang, Justin M Drake.

Prostate cancer is the most common non-cutaneous cancer among men in the United States. Most prostate cancers are driven by androgen receptor (AR) signaling, but there are an increasing number of cases that lose AR and gain neuroendocrine (NE) features (AR-/NE+) or lack both (AR-/NE-). These latter subtypes are particularly aggressive and lethal. Extracellular vesicles (EVs) have shown great potential as biomarkers for noninvasive liquid biopsy assays, as EVs contain biomolecules from their cells of origin. Here, we used a shotgun proteomics approach with mass spectrometry to interrogate the global proteome of EVs isolated from prostate cancer cell lines reflecting diverse clinical subtypes, including AR-/NE+ and AR-/NE- models. We identified 3,952 EV proteins, which clustered largely by tumor subtype and provided enough proteomic coverage to derive classic gene signatures of AR or NE identity that are of high relevance for prostate cancer prognostication. EVs isolated from AR+ cells displayed high levels of proteins regulated by AR and mTOR signaling. EVs isolated from AR-/NE+ cells contained known NE markers such as SYP and CHGA, whereas EVs from AR-/NE- models were enriched in basal cell markers and proteins that regulate epithelial-to-mesenchymal transition (EMT). We integrated our cell line data with recently published EV proteomics data from 27 advanced prostate cancer patients and found 2,733 overlapping proteins including cell surface markers relevant to prostate cancer, AR activity indicators, and proteins enriched in specific subtypes (AR+, AR-/NE-, AR-/NE+). This approach is especially promising for rare cancer subtypes, such as prostate cancers that lose AR-related features and gain NE features, so as to optimize the use of these liquid biopsy samples for clinical decision making.

DOI: https://doi.org/10.1101/2025.07.31.667906
Cancer Res. 2025 Aug 08.

Caloric Restriction Enhances the Efficacy of Anti-Androgen Therapy in Prostate Cancer by Inhibiting Androgen Receptor Translation.

Ricardo A Cordova, May Elbanna, Christopher Rupert, Sabrina A Orsi, Noah R Sommers, Angela J Klunk, Li Shen, Jagannath Misra, Jocelyne N Hanquier, Maria Tsompana, Yanqing Wang, David W Goodrich, Ronald C Wek, Luigi Fontana, Kirk A Staschke, Roberto Pili.

Epidemiological studies suggest that diet can impact the incidence, progression, and response to treatment in multiple cancers, including prostate cancer (PCa). In this study, we investigated the use of dietary interventions, specifically caloric or protein restriction, in combination with anti-androgen therapy as a treatment for PCa. Caloric restriction through alternate-day fasting (ADF) reduced androgen receptor (AR) expression and signaling. This reduction in AR enhanced the anti-tumor activity of the AR antagonist enzalutamide in multiple mouse models of PCa. Mechanistic studies revealed that nutrient starvation via ADF predominantly decreased AR mRNA translation at the elongation stage due to amino acid limitation. Pharmacological agents that similarly impair translation elongation and promote ribosome collisions mimicked the AR translation reduction observed with ADF. Overall, these findings suggest that amino acid limitation through ADF impairs translation elongation in PCa, to which AR mRNA translation is susceptible, leading to a reduction in AR protein levels and enhancing AR-targeted therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1986
Cell Discov. 2025 Aug 05. 11(1): 67

AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.

Sangsang Li, Yifan Zhang, Maoxing Luo, Weiwei Zhou, Yitong Chen, Dinglan Wu, Qiang Wei, Yan Chang, Hailiang Hu.

Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is known about the underlying molecular mechanisms, particularly the metabolic underpinnings. In this study, we demonstrated that the tryptophan catabolism-related tryptophan 2,3-dioxygenase (TDO2) -kynurenine (Kyn) -aryl hydrocarbon receptor (AhR) signalling axis was responsible for both sustaining the survival of dormant prostate cancer cells induced by androgen deprivation therapy (ADT) and promoting the reactivation of dormant cells and their recurrent outgrowth, which facilitated the development of therapeutic resistance by allowing the dormancy-to-reactivation switch. Mechanistically, we found that ADT upregulated the expression of TDO2 to produce Kyn, which activated AhR and maintained the survival of ADT-induced dormant cells. Interestingly, the switch of transcription factors from the androgen receptor (AR) to the glucocorticoid receptor (GR) modulated the persistent expression of TDO2 and promoted the reactivation of dormant cells through the same TDO2-Kyn-AhR signalling axis. Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT.

DOI: https://doi.org/10.1038/s41421-025-00817-w
bioRxiv. 2025 Jul 22. pii: 2024.08.26.609679. [Epub ahead of print]

Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion.

Fen Ma, Sen Chen, Luigi Cecchi, Betul Ersoy-Fazlioglu, Joshua Russo, Seiji Arai, Seifeldin Awad, Carla Calagua, Fang Xie, Larysa Poluben, Olga Voznesensky, Anson Ku, Fatima Karzai, Changmeng Cai, David Einstein, Huihui Ye, Xin Yuan, Alex Toker, Mary-Ellen Taplin, Adam G Sowalsky, Steven Balk.

The TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under the androgen receptor (AR) regulated expression of TMPRSS2. The T:E fusion is frequently associated with PTEN loss, and is highly correlated with decreased expression of INPP4B, both of which may compensate for ERG-mediated suppression of PI3K/AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses AKT activation, and that one potential mechanism is through downregulation of IRS2. In contrast, ERG knockdown did not increase INPP4B, suggesting its decreased expression is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is similarly decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a function distinct from regulation of PI3K activity. As ERG expression in T:E fusion tumors is AR regulated, we further assessed the extent to which AR inhibition increased AKT activity in T:E fusion tumors. T:E fusion positive versus negative PDXs had greater increases in AKT activity after castration. Moreover, in a neoadjuvant trial of AR inhibition prior to radical prostatectomy we similarly found greater increases in AKT activation in the T:E fusion tumors. Together these findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.

DOI: https://doi.org/10.1101/2024.08.26.609679
Discov Oncol. 2025 Aug 07. 16(1): 1497

Transcriptomic and functional analysis of triphenyl phosphate exposure in prostate cancer progression.

Li Cai, Guizhi Du.

   BACKGROUND: Prostate cancer is a common malignancy in men with variable clinical outcomes. While therapeutic options have improved, the potential impact of environmental chemicals such as Triphenyl phosphate (TPP)-a widely used organophosphorus flame retardant-on prostate cancer progression remains poorly understood.
METHODS: We conducted transcriptomic profiling using mRNA sequencing to investigate gene expression changes in prostate cancer cells following TPP exposure. Subsequent analyses, including single-sample gene set enrichment analysis (ssGSEA) and data mining from the Comparative Toxicogenomics Database (CTD), were performed to identify TPP-associated genes. TCGA-based survival modeling was used to evaluate the prognostic relevance of selected genes. Functional assays were carried out to assess TPP-induced phenotypic changes.
RESULTS: Exposure to 0.1 µM TPP significantly enhanced prostate cancer cell proliferation and invasion. Transcriptomic analysis revealed 521 upregulated and 964 downregulated genes post-treatment. Key prognostic markers, including TTK, S100A9, MACIR, AKR1B10P1, and ZFPM2-AS1, were identified and found to be associated with poor patient survival. GSEA further revealed that these genes are enriched in pathways related to metabolism and cancer progression.
CONCLUSION: Our findings suggest that TPP exposure may promote malignant phenotypes in prostate cancer cells by altering gene expression and activating cancer-associated pathways. This study underscores the potential health risks of environmental pollutants and highlights candidate prognostic biomarkers in prostate cancer.

Keywords:  Environmental exposures; Prognostic markers; Prostate cancer; Transcriptomics; Triphenyl phosphate

DOI:  https://doi.org/10.1007/s12672-025-03325-1
Mol Cancer Res. 2025 Aug 05.

Tumor Cholesterol Synthesis, Statin Use, and Lethal Prostate Cancer.

Sinead Flanagan, Rosina T Lis, Ying Huang, Lina Jehane, Jane B Vaselkiv, Emma H Allott, Stephen P Finn, Tamara L Lotan, Michelangelo Fiorentino, Massimo Loda, Gwo-Shu Mary Lee, Goutam Chakraborty, Philip W Kantoff, Lorelei A Mucci, Konrad H Stopsack.

Prostate tumor cells produce cholesterol de novo, and statin therapy targets the initial rate-limiting enzyme in this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). The extent to which the expression of HMGCR in prostate tumors could influence progression and predict the potential anti-neoplastic effects of statins remains unclear. In a prospective cohort study of 1098 men diagnosed with primary prostate cancer in 1982-2009 from the Health Professionals Follow-up Study and Physicians' Health Study, 16% of prostate tumors showed strong HMGCR staining intensity and 31% no staining. HMGCR expression was higher in tumors with PTEN loss but did not differ by statin use or long-term dietary cholesterol or saturated fat intake. Participants were followed for lethal events (distant metastases or prostate cancer-related death) over up to 32 years, and 96 lethal events occurred in those without metastases at diagnosis. Strong HMGCR expression was associated with higher rates of lethal prostate cancer (hazard ratio 2.2, 95% confidence interval 1.3-3.7), adjusting for age at diagnosis and Gleason score but without a linear dose response. In vitro in the LNCaP human prostate cancer cell line, atorvastatin impacted tumor cell viability in cells with experimentally lowered HMGCR expression. This study corroborates that high cholesterol synthesis in prostate tumor cells is associated with PTEN loss, aggressive tumor characteristics, and a greater risk of lethality. Implications: High expression of HMGCR, the first rate-limited enzyme of cholesterol synthesis, is a feature of prostate tumors that are more likely to progress to metastatic disease or death from prostate cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0864
Cell Death Dis. 2025 Aug 05. 16(1): 591

SLC7A11 upregulation via AR and NEDD4L ubiquitination contributes to ferroptosis inhibition and enzalutamide resistance in castration-resistant prostate cancer.

Min Tang, Luotong Xue, Bao Wang, Zhixin Jiang, Pu Li, Hengtao Bu, Chesong Zhao, Yurong Zhang, Shuaimei Liu, Xiyuan Chen, Bianjiang Liu, Xiaoxin Meng, Jie Li.

Advanced prostate cancer (PCa) is associated with a poor prognosis, particularly in patients who progress to castration-resistant prostate cancer (CRPC). The emergence of enzalutamide (Enz), a second-generation androgen receptor inhibitor, has effectively extended the median survival of these patients. However, drug resistance frequently develops during clinical use. Multiple studies have suggested that ferroptosis inducers can reverse cancer resistance to Enz, though the exact mechanisms remain unclear. In this study, we found that CRPC cells exhibit a concentration-dependent decrease in ferroptosis in response to Enz. This change is attributed to the upregulation of the protein level of SLC7A11. Protein stability assays and database analyses showed that SLC7A11 undergoes post-translational modification, likely connected to Enz-mediated downregulation of the SLC7A11-specific E3 ubiquitin ligase NEDD4L. This phenomenon was significantly reversed by the addition of erastin, a targeted inhibitor of the cystine/glutamate transport system Xc-. The data from both in vitro and in vivo experiments indicate that combining Enz with erastin significantly inhibits the proliferation of drug-resistant CRPC cells, thereby enhancing tumor suppression. These findings offer novel insights into targeting SLC7A11 with erastin as a potential strategy to overcome Enz resistance.

DOI: https://doi.org/10.1038/s41419-025-07809-4
Front Pharmacol. 2025 ;16 1606914

Integrative genomic analysis identifies DPP4 inhibition as a modulator of FGF17 and PDGFRA downregulation and PI3K/Akt pathway suppression leading to apoptosis.

Kiran Kumar Chitluri, Emerson Isaac Arnold.

   Introduction: Prostate cancer (PCa) remains a significant global health challenge despite advancements in treatment strategies. There is a need to explore the molecular heterogeneity of PCa to facilitate the development of personalized treatment approaches. This study investigates the molecular heterogeneity of PCa by combining genomic and transcriptomic data using a systems biology approach.
Methods: By utilising whole-genome sequencing and differentially expressed genes from "The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD)" patient samples, we identified 357 intersecting genes. From protein-protein interaction network analysis, 22 hub genes were identified as critical regulators associated with PCa prognosis and pathogenesis. Furthermore, these hub genes were subjected to functional and pathway enrichment analysis via gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG).
Results: Notably, the PI3K/Akt signalling pathway was significantly enriched with eight of these hub genes, with significant clinical relevance. Dipeptidyl Peptidase 4 (DPP4) emerged as a promising therapeutic target. Further, in vitro assays were performed to investigate and validate the molecular role of DPP4 through pharmacological inhibition using Linagliptin, a selective DPP4 inhibitor. Inhibition of DPP4 led to the induction of apoptosis, G1/S phase cell cycle arrest, and significant suppression of cell proliferation and migration in PC3 and DU145 cell lines.
Discussion: These experiments revealed novel downstream regulatory effects of DPP4, demonstrating that its inhibition results in the transcriptional downregulation of FGF17, PDGFRA, COL4A1, and COL9A2, thereby contributing to the inactivation of the PI3K/Akt signaling pathway. Collectively, these findings highlight DPP4 as a potential therapeutic target for the treatment of PCa.

Keywords:  DPP4/CD26; DU145; Linagliptin; PC3; PI3K/Akt pathway; apoptosis; mutation; prostate cancer

DOI:  https://doi.org/10.3389/fphar.2025.1606914
Reprod Biol. 2025 Aug 04. pii: S1642-431X(25)00060-9. [Epub ahead of print]25(3): 101053

The impact of dexamethasone on cellular stress responses caused by mild serum deprivation in androgen-insensitive prostate cancer cells.

Weronika Broszkiewicz, Jakub Beda, Kamila Domińska.

  Dexamethasone (DEX), a glucocorticoid receptor agonist, is widely used for prostate cancer therapies, although its exact impact on androgen-independent prostate cancer cells remains unclear. As solid cancers are typically characterized by nutrient-deprived conditions in the tumor microenvironment (TME), the present study examines the effect of DEX on stress responses in DU-145 and PC3 cells caused by mild serum deficiency. It was found that DEX limited the ability of prostate cancer cells to divide and deepened the G0 / G1 cell cycle arrest induced by serum deprivation; it also reduced adhesion by DU-145 and PC3 cells to extracellular matrix proteins, but did not increase migration. However, it improved the survival of androgen-insensitive prostate cancer cells under conditions of mild serum deprivation by preventing apoptosis, reprogramming the glucose and lipid metabolism and restoring the inflammatory balance. We postulate that dexamethasone has a cytostatic rather than cytotoxic effect on androgen-independent prostate cancer cells and that it directs prostate cancer cells to a resting state. Treatment also carries a risk of minimal residual disease (MRD).

Keywords:  DU-145; Dexamethasone; PC3; Prostate cancer; Serum starvation

DOI:  https://doi.org/10.1016/j.repbio.2025.101053
Cancer Res. 2025 Aug 04.

Integrated Omics and Multi-Cohort Analyses Identify an Enhancer Variant Linking Ferroptosis to Precision Therapy in Prostate Cancer.

Sheng Ma, Yue Ge, Zequn Lu, Junbiao Zhang, Qin Zhang, Yuzheng Peng, Zirui Xi, Hao Peng, Meng-Yao Xu, Zezhong Xiong, Yuan Gao, Yanan Wang, Le Li, Chunyu Zhang, Zheng Chao, Tengfei Li, Ruiyun Zhang, Qiang Zhang, David A Horne, Baojun Wang, Xu Gao, Xu Zhang, Jianbo Tian, Jing Li, Meng Jin, Gong-Hong Wei, Zhihua Wang.

Prostate cancer is the most prevalent cancer among men worldwide and exhibits significant genetic heritability. In this study, we performed an integrative analysis combining chromatin accessibility profiling, transcriptomics, and two-stage case-control studies, alongside an unbiased phenome-wide exploration in the FinnGen cohort. This comprehensive approach identified the enhancer-associated single-nucleotide polymorphism rs7077830 at chromosome 10q11 as a critical modulator of prostate cancer susceptibility. Mechanistic investigations revealed that rs7077830 exerted allele-specific enhancer activity, driving NCOA4 expression via a ZNF384-mediated enhancer-promoter interaction. CRISPR/Cas9-mediated single-nucleotide editing confirmed the direct regulatory role of rs7077830 on NCOA4 and its contribution to prostate cancer progression. Functional studies demonstrated that NCOA4 acted as a tumor suppressor by promoting ferroptosis. Furthermore, NCOA4 expression modulated sensitivity to ferroptosis-inducing agents. Strikingly, rs7077830 genotypes were directly linked to ferroptosis status in prostate cancer. These findings highlight the role of noncoding genetic variants in prostate cancer pathogenesis, provide insights into enhancer-driven ferroptosis regulation, and suggest a promising therapeutic avenue for prostate cancer patients carrying specific rs7077830 genotypes.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-5018
Nitric Oxide. 2025 Aug 04. pii: S1089-8603(25)00065-5. [Epub ahead of print]

Nitric Oxide Tuning Enhances Cytotoxicity and Reduces Inflammation in Prostate Cancer Nanotherapy.

Joana Claudio Pieretti, Giovana Marchini Armentano, Marcela Sorelli Carneiro-Ramos, Amedea Barozzi Seabra.

  Modulating intracellular nitric oxide (NO) levels offers a promising strategy to enhance tumor cell sensitivity to nanoparticle-based therapies. In this study, we investigated the impact of intracellular NO modulation in prostate cancer cells (PC3) using S-nitrosoglutathione (GSNO, a NO donor) and L-nitro arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor), in combination with cisplatin-loaded zinc oxide nanoparticles (ZnO/CisPt NPs). These nanoparticles, previously shown to exert selective cytotoxicity against PC3 cells, had their therapeutic performance further enhanced by NO modulation, which led to reduced NOS expression and regulation of inflammatory cytokines. Interestingly, both the increase and the depletion of intracellular S-NO levels contributed to tumor cell sensitization to the nanoparticle-based treatment. These results indicate that altering NO balance, regardless of direction, plays a key role in how cells respond to therapy. Our results reinforce the relevance of NO signaling in augmenting the efficacy of nanomedicine approaches while minimizing tumor-associated inflammation, offering a safer and more targeted strategy for prostate cancer treatment with potential for broader applications in oncology.

Keywords:  inflammation; nitric oxide modulation; nitric oxide synthase; prostate cancer; zinc oxide nanoparticles

DOI:  https://doi.org/10.1016/j.niox.2025.08.001
Urologia. 2025 Aug 06. 3915603251360527

Advances in targeted therapies by PARP inhibitors for the treatment of prostate cancer: A scientometric approach.

Iman Menbari Oskouie, Naghmeh Khavandgar, Hediyeh Alemi, Heydar Ali Mardani-Fard, Amir-Hossein Mousavian, Maryam Noori, Azadeh AleTaha, Akbar Soltani, Fateme Guitynavard, Seyed Reza Yahyazadeh, Amir Kasaeian.

   INTRODUCTION: The most prevalent cancer in men is prostate cancer (PCa). One significant discovery involves attacking tumors with mutations in DNA damage repair genes via the blockage of poly(ADP-ribose) polymerase (PARP) enzymes. In this study, we provide a summary of the present research status of PARP inhibitors in PCa, highlighting areas of interest and emerging trends.
METHOD: Our search covered the Scopus database for literature on PARP inhibitors in PCa up to the year 2023. We conducted a scientometric review using VOSviewer to evaluate the output across countries, institutions, authors, journals, references, and keywords.
RESULTS: The study included 1850 articles on PARP inhibitors in prostate cancer (PCa) published until 2023, with medicine, biochemistry, and pharmacology being the most represented subject areas. The United States led in publication volume (n = 800, 43.2%), followed by the United Kingdom (n = 281, 15.2%) and China (n = 198, 10.7%), and also achieved the highest total citations and H-index. A positive correlation was identified between publication volume and gross domestic product (GDP; r = 0.843, p < 0.001). Antonarakis, E.S., from the United States, ranked as the most prolific author (49 publications) and achieved the highest H-index, while Mateo, J. was the most cited. The Institute of Cancer Research emerged as the most active institution, publishing 91 articles, and the journal Cancers contributed the highest number with 99 articles. In keyword analysis, "prostate cancer" and "PARP inhibitors" were the most used terms, forming six thematic clusters. Citation and co-citation analysis highlighted the influential role of high-impact journals like New England Journal of Medicine and Journal of Clinical Oncology.
CONCLUSION: The United States has taken the lead in this sector by making the largest contribution in terms of overall publications. Although international partnerships are occurring globally, there is a need for more assistance and expansion of research on PAPR inhibitors in PCa, particularly in underdeveloped nations. This study offers assistance to medical professionals, scientists, and surgery assistants on the worldwide results of PAPR inhibitors in PCa research.

Keywords:  PARP inhibitors; bibliometric; prostate cancer; scientometric

DOI:  https://doi.org/10.1177/03915603251360527
Oncogene. 2025 Aug 02.

PKA-driven SPP1 activation as a novel mechanism connecting the bone microenvironment to prostate cancer progression.

Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D A Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino.

Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or C42B/MC3T3 cell lines), and in vivo, using cell lines' engraftments and patient-derived xenografts (PDX) grown intrafemorally. Importantly, clinical data from longitudinal patient samples revealed that treatment with enzalutamide, an androgen receptor (AR) inhibitor, led to an increase in PKA signaling and corresponding SPP1 expression in a subpopulation of patients, highlighting the relevance of the PKA/SPP1 axis in disease progression under AR-targeted therapies. Overall, we underscored the critical role of the bone microenvironment in influencing PCa progression, pointing out to SPP1/OPN as a biomarker for identifying tumors with active PKA signaling, which could serve to manage resistance to AR-directed treatments.

DOI: https://doi.org/10.1038/s41388-025-03511-z
J Biochem Mol Toxicol. 2025 Aug;39(8): e70425

Integrated Transcriptomic and Metabolomic Analyses in Characterizing the Anti-Prostate Cancer Effects of Hederagenin.

Tong Cai, Weigui Sun, Shanyi Li, Fangmin Liu, Rong Hu, Yanjuan Wang, Wenji Li.

  Hederagenin is a triterpenoid compound extracted from ivy leaves and other natural plant sources. Despite the prominent roles that hederagenin assumes in the fight against cancers, its mechanisms in anti-prostate cancer (PCa) remain inadequately comprehended. In this present study, we found that hederagenin effectively inhibited the proliferation and migration of PCa cells by inducing apoptosis in a dose-dependent manner. Transcriptome analysis and metabolic alterations were employed to identify potential molecular targets and pathways of Hederagenin on PCa cells. RNA-seq analysis discerned 747 differentially expressed genes (DEGs) that were conspicuously enriched within the pathway. Furthermore, metabolomics analysis has revealed that hederagenin significantly impacts the metabolic pathways, specifically in glycerophospholipids, choline metabolism, cholesterol metabolism and autophagy. Finally, we carried out the integrated analysis of the metabolomic data and transcriptomic data and validated them by qRT-PCR and western blot experiments. The transmission electron microscopy (TEM) analysis revealed an augmented generation of autophagosomes in PC-3 cell under treatment with hederagenin. The results indicated that hederagenin significantly increased the expression levels of LC3-II/I and P62 in both PCa cells following co-treatment with chloroquine (CQ). Additional functional analysis demonstrated that the inhibition of autophagy by CQ significantly augmented hederagenin-induced apoptotic cell death. The findings suggest that hederagenin efficaciously elicited apoptosis and autophagy of PCa via the mTOR pathway. In conclusion, we believe our study would provide a systematic perspective on the therapeutic effect of hederagenin, which could contribute to the clinical application of hederagenin combined with autophagy inhibitors as a novel strategy for treating human PCa.

Keywords:  autophagy; hederagenin; metabolomics; prostate cancer; transcriptomics

DOI:  https://doi.org/10.1002/jbt.70425
J Biol Chem. 2025 Aug 02. pii: S0021-9258(25)02311-7. [Epub ahead of print]301(8): 110461

The kinesin-14 family motor protein KIFC2 promotes prostate cancer progression by regulating p65.

Xinyu Liu, Yu Lin, Weibing Long, Renzheng Yi, Xiongfeng Zhang, Chaoqun Xie, Na Jin, Ziran Qiu, Xiaobing Liu.

DOI: https://doi.org/10.1016/j.jbc.2025.110461
J Transl Med. 2025 Aug 07. 23(1): 885

SREBF1-mediated SND1 transcriptional activation promotes prostate cancer progression via MTDH interaction through the SESN2/AMPK/mTOR axis.

Yijie Tang, Yufan Ying, Xueyou Ma, Jiahe Yi, Zixiang Liu, Yuqing Wu, Shen Lin, Xuan Shu, Zhixiang Qi, Jindan Luo, Xiangyi Zheng, Jiangfeng Li, Liping Xie, Ben Liu.

   BACKGROUND: Prostate cancer (PCa) is a prevalent cancer and a major cause of cancer-related deaths in men worldwide. Growing evidence indicates that Staphylococcal nuclease and Tudor domain containing 1 (SND1) is a multifunctional protein extensively involved in transcriptional regulation, RNA maturation, post-transcriptional modifications, and other processes. However, previous studies have rarely investigated the function of SND1 as an RNA-binding protein in PCa tumorigenesis.
METHODS: The Cancer Genome Atlas and NCBI Gene Expression Omnibus (GEO) databases were used to evaluate SND1 expression levels in PCa. We conducted a series of in vitro and in vivo functional experiments to assess the biological functions of SND1, including cell counting kit-8, colony formation, Transwell and wound-healing assays, and animal experiments in nude mice. Chromatin immunoprecipitation, dual-luciferase reporter assay, and DNA pull-down assay were performed to validate the association between the upstream transcription factor and SND1. Based on mass spectrometry, RNA-seq, and RNA immunoprecipitation (RIP)-seq, we identified the downstream targets of SND1- Sestrin 2 (SESN2), which were validated through qRT-PCR, Western blotting, RIP-qPCR, dual-luciferase reporter assay, and RNA pull-down assay. Finally, a series of functional assays and Western blotting analyses confirmed SESN2 as a downstream target of SND1.
RESULTS: Our research identified that SND1 was significantly elevated in PCa, and knocking down SND1 repressed PCa multiplication and migration. Mechanistically, sterol regulatory element binding transcription factor 1 (SREBF1) bound to the promoter of the SND1 gene and activated its transcription, which subsequently formed a complex with metadherin (MTDH). This complex is directly bound to and degraded SESN2 mRNA, and disruption of this interaction with C26-A6 inhibited MTDH-SND1-mediated SESN2 degradation. Notably, SESN2 expression was inhibited in PCa and may exert tumor-suppressive effects by affecting the AMPK/mTOR signaling pathway. Rescue experiments indicated that knocking down SND1 or MTDH significantly inhibited PCa proliferation and migration, and knocking down SESN2 partially reversed this effect.
CONCLUSIONS: Our study reveals SND1 overexpression in PCa, which is transcriptionally activated by SREBF1. Mechanistically, SND1 interacts with MTDH and promotes SESN2 mRNA degradation, modulating PCa progression through the AMPK/mTOR pathway.

Keywords:  MTDH; Prostate cancer; SESN2; SND1; mTOR

DOI:  https://doi.org/10.1186/s12967-025-06762-2
Int J Oncol. 2025 09;pii: 77. [Epub ahead of print]67(3):

Cuproptosis in prostate cancer: Molecular mechanisms, prognostic biomarkers and therapeutic frontiers of cuproptosis‑related genes (Review).

Zhugang Long, Yue Chang, Kun Zhu, Zhengyang Chen, Yaodong You.

  Prostate cancer (PCa) is among the most prevalent malignancies in males globally and management remains complex. In recent years, cuproptosis, an emerging form of cell death, has offered novel insights for PCa treatment. Cuproptosis refers to a copper‑mediated cellular death mechanism that is intricately associated with mitochondrial metabolism, with cuproptosis‑related genes (CRGs) exerting a notable effect on both cuproptosis and PCa. CRGs and other cuproptosis‑associated indicators have demonstrated efficacy as prognostic predictors of PCa and these predictors may exhibit potential as novel therapeutic targets in the treatment of PCa. The mechanisms underlying cuproptosis in PCa remain to be fully elucidated; thus, further research is required to validate the expression patterns of CRGs and their associated indicators and examine the potential association with the characteristics, treatment responses and prognoses of patients with PCa. The present study aimed to investigate novel therapeutic strategies that may enhance the prognosis and quality of life of patients with PCa.

Keywords:  cell death; copper metabolism; cuproptosis; cuproptosis‑related genes; prostate cancer

DOI:  https://doi.org/10.3892/ijo.2025.5783