bims-meproc 2025-05-11 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–05–11
ten papers selected by
Grigor Varuzhanyan, UCLA

The PPARβ/CERK/C1P signaling pathway is a potential mechanism by which antimony exposure promotes prostate cancer cell proliferation.
Targeting RBP4-STRA6 retinol signaling disrupts adipose-prostate crosstalk: A novel strategy to suppress basal cell plasticity in androgen deprivation.
Assessing the potential for in vivo modulation of FTH1 gene expression with small peptides to restore and enhance androgen receptor pathway inhibition in prostate cancer.
Insights into the cellular lipid cascade of prostate cells explored using infrared microspectroscopy.
Sinularin induces autophagy-dependent cell death by activating ULK1 and enhancing FOXO3-ATG4A axis in prostate cancer cells.
CASK promotes prostate cancer progression via kinase-dependent activation of AKT.
The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer.
Prostate cancer and metabolic syndrome: exploring shared signature genes through integrative analysis of bioinformatics and clinical data.
Association Aamong Ppolymorphisms in the Aapoptosis-Rrelated NKX3-1, Caspase-3, Caspase-9, and BCL-2 Genes and Prostate Cancer Susceptibility From 9706 Cases and 12,567 Controls.
Network Pharmacology and Molecular Dynamics Identified Potential Androgen Receptor-Targeted Metabolites in Crocus alatavicus.

Ecotoxicol Environ Saf. 2025 May 05. pii: S0147-6513(25)00604-9. [Epub ahead of print]297 118268

The PPARβ/CERK/C1P signaling pathway is a potential mechanism by which antimony exposure promotes prostate cancer cell proliferation.

Jianxi Shi, Zhaopeng Li, Xiaoyu Sun, Duo Zhao, Shaosan Kang, Fenghong Cao, Zhihong Zhang, Changwen Zhang.

  Prostate cancer (PCa) is the most common malignant tumor in males. Antimony (Sb) is a widespread industrial heavy metal pollutant listed as a Class IIB carcinogen by the International Agency for Research on Cancer (IARC). Previous work found that antimony exposure can promote the proliferation of prostate cancer cells, but the relevant molecular mechanisms have not been fully explored. Lipid metabolomic sequencing revealed that ceramide levels were significantly elevated in PCa cells after low-dose antimony exposure. To explore the relationship between antimony exposure and cell proliferation, we found that the level of ceramide-1-phosphate (C1P), one of the metabolites of ceramide, increased after antimony exposure, and C1P can promote the proliferation of prostate cancer cells and antagonize the apoptosis induced by ceramide. Mechanism exploration shows that antimony exposure activates peroxisome proliferator-activated receptor beta (PPARβ), up-regulates the expression levels of ceramide transport protein (CERT) and ceramide kinase (CERK), promotes the conversion of Cer to C1P, thereby inhibiting apoptosis and promoting PCa cells proliferation. In addition, we also found that C1P can partially inhibit ferroptosis induced by erastin. These findings indicate that C1P is closely related to antimony-induced PCa proliferation and may be a potential biomarker of PCa.

Keywords:  Antimony; Ceramide; Ceramide 1-phosphate; Ferroptosis; Prostate cancer

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118268
Metabolism. 2025 May 06. pii: S0026-0495(25)00157-X. [Epub ahead of print]169 156288

Targeting RBP4-STRA6 retinol signaling disrupts adipose-prostate crosstalk: A novel strategy to suppress basal cell plasticity in androgen deprivation.

Huan Xu, Dajun Gao, Yanting Shen, Jianqing Wang, Junduo Wang, Jun Zhu, Miao Ren, Lai Wei, Hailiang Hu, Ming Zhan, Zhong Wang, Fubo Wang, Bin Xu.

  Metabolic rewiring is a starter for lineage plasticity, which is an important driver of prostate development, tumorigenesis and treatment resistance. Androgen-targeted therapies are central to prostate cancer (PCa) management, yet the mechanisms leading prostate development-particularly the metabolic signaling within basal cells during treatment-remain poorly understood. To fulfill this gap, we used multiple models to reveal the metabolic alterations in prostate basal cells. Our study reveals the role of the RBP4-STRA6 axis in modulating retinol metabolism and transporting retinol from adipocyte into prostate cells, contributing to prostate development and basal cell differentiation during androgen deprivation. Through multi-omics analyses, we demonstrate that RBP4-STRA6 axis dependent retinol metabolism is increased with androgen deprivation. Retinol metabolism rewiring is modulated by the androgen receptor (AR) and can regulate basal cell plasticity under androgen deprivation therapy (ADT). Retinol metabolism maintains prostate basal cell lineage plasticity during hormone therapy through the PPARγ signaling pathway, compensating for the AR signaling pathway inhibition by sustaining energy homeostasis and promoting basal cell differentiation. Notably, we identified a basal cell cluster (BC5) characterized by high Retinol metabolism and activated PPARγ signaling pathway, which plays a crucial role in basal-luminal differentiation and prostate growth. This study underscores the importance of RBP4-STRA6 dependent Retinol metabolism, mediating the crosstalk between adipocytes and prostate basal cells, in maintaining prostate development during hormone therapy and provides a foundation for future clinical interventions and diet strategies aimed at enhancing the sensitivity of androgen deprivation in prostate diseases.

Keywords:  Androgen deprivation; Basal cell differentiation; PPAR; Prostate; Retinol

DOI:  https://doi.org/10.1016/j.metabol.2025.156288
Cancer Biol Ther. 2025 Dec;26(1): 2503417

Assessing the potential for in vivo modulation of FTH1 gene expression with small peptides to restore and enhance androgen receptor pathway inhibition in prostate cancer.

Crawford Currie, Christian Bjerknes, McKayla Nicol, Sateesh Kumar, Bomi Framroze.

  Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.

Keywords:  Advanced prostate cancer; FTH1; TFRC; androgen receptor inhibitor; c-MYC; ferroportin; hepcidin; labile iron pool

DOI:  https://doi.org/10.1080/15384047.2025.2503417
Analyst. 2025 May 06.

Insights into the cellular lipid cascade of prostate cells explored using infrared microspectroscopy.

Thomas A Gladwell, Dougal Ferguson, Noel Clarke, Michael D Brown, Peter Gardner.

Background: Although prostate cancer (PCa) is the most diagnosed cancer in men worldwide, there is geographical variance in both incidence and morbidity, with higher levels in developed "Western Diet" countries. In particular the high levels of the omega-6 polyunsaturated fatty acid, arachidonic acid (AA), in Western diets has been shown to promote aggressive PCa in vitro. However the exact mechanism through which AA induces the aggressive phenotype has not been fully characterised. Methods: In this study Fourier transform infrared (FTIR) imaging coupled with fluorescence microscopy (FM), is used to follow AA metabolism in PCa cell lines. This is achieved using partially deuterated AA, with a distinctive C-D stretch seen at 2251 cm-1 providing molecular specificity, coupled with Nile Red Fluorescence imaging. Results: We show that, invasive cell lines PC-3, LNCaP C4-2B and DU145 readily uptake and metabolise AA, producing prostaglandins via the COX-2 pathway. Inhibition of the COX-2 pathway with either NS938 or the omega-3 polyunsaturated fatty acid Docosahexaenoic acid (DHA), reduces the invasive stimulus of AA and blocks its uptake. Conclusion: This demonstrates that FTIR imaging can be utilised to follow metabolomics processes within a PCa model and provide an insight to the molecular pathways underlying the cancer metabolome. Additionally, these works provide key insights into the rapid uptake of AA within certain invasive cell lines of prostate cancer, suggesting that AA exposure initiates early cellular responses prior to the uptake and processing of lipids within the cells.

DOI: https://doi.org/10.1039/d5an00126a
Sci Rep. 2025 May 07. 15(1): 15875

Sinularin induces autophagy-dependent cell death by activating ULK1 and enhancing FOXO3-ATG4A axis in prostate cancer cells.

Xiang-Yu Meng, Yi Li, Ze-Jun Yan, Sha-Zhou Ye, Ke-Jie Wang, Jun-Feng Chen, Rui Yu, Qi Ma.

  Sinularin is a natural product extracted from soft coral and is shown to exhibit antitumor effects against multiple human cancers. We previously showed that Sinularin induces apoptotic cell death via stabilizing the FOXO3 protein in prostate cancer cells. In this study, we demonstrated that Sinularin triggers autophagy via two different mechanisms in prostate cancer cells. First, Sinularin reduced the S757 phosphorylation of ULK1 protein, which was mediated by mTOR, leading to ULK1 activation and autophagy initiation. Second, Sinularin enhanced the expression of autophagic protein ATG4A, which is the key regulator in the formation of autophagosome, through a FOXO3-dependent transcriptional mechanism. Next, we identified that ATG4A is a new target gene of the transcription factor FOXO3. Additionally, we also found that Sinularin-induced autophagy promoted survivin degradation and led to cell apoptosis. Taken together, these findings suggest that Sinularin induces prostate cancer cell autophagy by promoting autophagy initiation through activation of ULK1 and formation of autophagosome through the FOXO3-ATG4A pathway.

Keywords:  Apoptosis; Autophagy; FOXO3; Prostate cancer; Sinularin

DOI:  https://doi.org/10.1038/s41598-025-00909-3
Int J Biol Macromol. 2025 May 05. pii: S0141-8130(25)04517-9. [Epub ahead of print]311(Pt 2): 143965

CASK promotes prostate cancer progression via kinase-dependent activation of AKT.

Varsha Rathore, Ching-Yuan Cheng, Shao-Peng Chen, Chia-Yee Lin, Chuang-Rung Chang, Wan-Wan Lin.

  Until now, the role of calcium/calmodulin-dependent serine protein kinase (CASK) in prostate cancer (PCa) progression remains unknown. In this study, we investigated the roles of CASK in PCa progression, cell migration, and invasion. We found that CASK is up-regulated in PCa tissues of patients. Lentivirus-based CASK silencing does not affect cell growth or serum-free-induced cell death in PC3 and LNCaP cells, regardless of the presence or absence of TGF-β. CASK silencing decreases cell migration and invasion, either in the absence or presence of TGF-β stimulation. Immunoblotting data indicate that CASK silencing does not alter TGF-β-induced Smad2/3 and ERK phosphorylation but reduces TGF-β-induced AKT phosphorylation. To understand the roles of AKT and CaMK-like activity of CASK in cellular responses in PCa cells, we treated cells with AKT inhibitor and specific kinase inhibitors of CASK (NR162) and CaMKII (KN-93). We found that these agents can inhibit cell invasion and migration. In addition, NR162 and KN-93 also reduce TGF-β-induced AKT phosphorylation. Moreover, the co-immunoprecipitation data indicate the association between CASK and AKT. In HEK293 cells overexpressing system, we further found that CASK can enhance AKT S473 phosphorylation. The tumorigenic effect of CASK is confirmed in the xenograft mouse system. In summary, CASK is a promoter of PCa progression and can enhance PCa cell migration and invasion via kinase-dependent AKT activation independent of TGF-β-induced Smad2/3 and ERK signaling.

Keywords:  AKT; CASK; CaMK; Invasion; Migration; TGF-β

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143965
Mol Cancer. 2025 May 05. 24(1): 134

The anti-diabetic PPARγ agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer.

Emine Atas, Kerstin Berchtold, Michaela Schlederer, Sophie Prodinger, Felix Sternberg, Perla Pucci, Christopher Steel, Jamie D Matthews, Emily R James, Cécile Philippe, Karolína Trachtová, Ali A Moazzami, Nastasiia Artamonova, Felix Melchior, Torben Redmer, Gerald Timelthaler, Elena E Pohl, Suzanne D Turner, Isabel Heidegger, Marcus Krueger, Ulrike Resch, Lukas Kenner.

  Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.

Keywords:  Cancer therapy; Energy metabolism; Extracellular acidification; Metabolic rewiring; Oxygen consumption rate; PPAR agonists; Type 2 diabetes mellitus (T2DM)

DOI:  https://doi.org/10.1186/s12943-025-02320-y
Discov Oncol. 2025 May 08. 16(1): 698

Prostate cancer and metabolic syndrome: exploring shared signature genes through integrative analysis of bioinformatics and clinical data.

Maomao Guo, Sudong Liang, Zhenghui Guan, Jingcheng Mao, Zhibin Xu, Wenchao Zhao, Hao Bian, Jianfeng Zhu, Jiangping Wang, Xin Jin, Yuan Xia.

  The incidence of both prostate cancer (PCa) and metabolic syndrome (MS) has been steadily increasing due to changes in population structure and lifestyle. These two conditions frequently co-occur, yet their shared pathogenic mechanisms remain unclear. In this study, we utilized bioinformatics and machine learning techniques to analyze public datasets and validated our findings using clinical specimens from our center to identify common signature genes between PCa and MS. We began by screening differentially expressed genes (DEGs) and module genes through Linear models for microarray analysis (Limma) and Weighted Gene Co-expression Network Analysis (WGCNA) of four microarray datasets from the GEO database (PCa: GSE8511, GSE32571, and GSE104749; MS: GSE98895). Comprehensively bioinformatics analyses, including functional enrichment, LASSO, and random forest algorithms, coupled with receiver operating characteristic (ROC) and precision recall curve (PRC) analyses were conducted. We identified 423 DEGs in the PCa dataset and 2481 differentially modular genes in the MS dataset. Among these, 52 intersection genes enriched in immunomodulatory pathways were found. Three common signature genes, namely GPD1L, ACY1, and C12orf75, were identified through LASSO and random forest analyses. Subsequent validation using clinical specimens confirmed differential expression of these genes in PCa, with survival analysis indicating that elevated expression of ACY1 is associated with adverse prognosis in PCa patients. Additionally, immunoinfiltration analysis revealed higher levels of macrophage M0 and activated dendritic cells in PCa tissues. In summary, our study identifies three shared signature genes between PCa and MS, with ACY1 demonstrating adverse prognostic significance in PCa. Our findings provide a foundation for elucidating the pathogenic mechanisms and interplay between PCa and MS, offering novel insights for identifying potential therapeutic targets in PCa.

Keywords:  Bioinformatics analysis; Immune infiltration; Metabolic syndrome; Prostate cancer

DOI:  https://doi.org/10.1007/s12672-025-02561-9
Cancer Rep (Hoboken). 2025 May;8(5): e70206

Association Aamong Ppolymorphisms in the Aapoptosis-Rrelated NKX3-1, Caspase-3, Caspase-9, and BCL-2 Genes and Prostate Cancer Susceptibility From 9706 Cases and 12,567 Controls.

Yanyan Feng, Zhenting Feng, Dan Li, Jiandong Gui, Zhihong Song, Xiaohua Xie, Lijie Zhu, Yuanyuan Mi.

   BACKGROUND: While there is a growing volume of evidence suggesting that relatively prevalent functional polymorphisms present within apoptosis-related genes may influence human prostate cancer (PCa) susceptibility, the clinical relevance of these findings remains inconclusive.
AIMS: This meta-analysis was thus developed with the goal of generating more precise estimates of the relationships between polymorphisms in four apoptosis-associated genes (NKX3-1, caspase-3, caspase-9, and BCL-2) and the risk of PCa.
METHODS AND RESULTS: The PubMed, Web of Science, Google Scholar, Embase, Cochrane Library, and SinoMed (CNKI and Wanfang) databases were searched for relevant studies published through December 20, 2023, using the following keywords: "polymorphism" or "variant" and "carcinoma" or "cancer" or "tumor" and "NKX3-1," "CASP3" or "Caspase-3," "CASP9" or "Caspase-9," "BCL-2" or "B-cell lymphoma" and "prostate cancer" or "PCa" or "prostate adenocarcinoma." This approach led to the identification of 22 case-control studies related to the association between apoptosis-related gene polymorphisms and PCa susceptibility enrolling 9706 cases and 12 567 controls. Subsequent analyses revealed that the NKX3-1 rs2228013, CASP9 rs1052571, and CASP9 rs4645982 polymorphisms were associated with greater PCa risk, whereas the CASP3 rs4647603 polymorphism was associated with a risk reduction.
CONCLUSION: These findings provide strong evidence for the potential contributions of polymorphisms in the apoptosis-related caspase-3, caspase-9, and NKX3-1 genes in the onset and progression of PCa.

Keywords:  BCL‐2; NKX3‐1; apoptosis‐related genes; caspase‐3; caspase‐9; meta‐analysis; polymorphisms; prostate cancer

DOI:  https://doi.org/10.1002/cnr2.70206
Int J Mol Sci. 2025 Apr 09. pii: 3533. [Epub ahead of print]26(8):

Network Pharmacology and Molecular Dynamics Identified Potential Androgen Receptor-Targeted Metabolites in Crocus alatavicus.

Zhen Ding, Yuanfeng Lu, Jichen Zhao, Daoyuan Zhang, Bei Gao.

  The objective of this study is to identify the active components of Crocus alatavicus and potential targets through a combination of network pharmacology, molecular docking technology combined with molecular dynamics simulation, and binding free energy analyses. A total of 253 active ingredients from C. alatavicus were screened, and 1360 associated targets were predicted through systematic searches conducted using TCMSP, SwissDrugDesign, and SymMap, which were integrated to construct a pharmacological network to dissect the relationships among active components, targets, diseases, and pathways; we found prostate cancer-related genes were significantly enriched among the targets. Subsequently, the core prostate cancer-related targets were identified in the network, and the binding interactions between protein targets and active components were evaluated using molecular docking technology. Furthermore, molecular dynamics simulation and binding free energy analyses were performed to verify the binding stability of the most promising complex. Then, protein-protein interaction network analysis was conducted to evaluate the core target sites, leading to the identification of nine target proteins with significant correlations, providing potential targets for cancer treatment. Furthermore, these targets were found to be associated with 20 signaling pathways, including neuroactive ligand-receptor interactions, prostate cancer, lipid metabolism and atherosclerosis, as well as calcium signaling pathways. The active component-target-disease-pathway network diagram suggests that Capillarisin, Eugenol, 1-(4-Methoxyphenyl)-1-propanol, 2,4,2',4'-tetrahydroxy-3'-prenylchalcone, and 4-Hydroxymandelonitrile may serve as key components targeting prostate cancer. Molecular docking analyses demonstrated that Capillarisin has a high affinity for the androgen receptor (AR), and molecular dynamics simulation was performed to further verify the binding stability, indicating that Capillarisin may exert its pharmacological effects in prostate cancer. Based on the integrated strategies of network pharmacology, molecular docking, molecular dynamics simulation, and binding free energy analysis, this study generated novel insights into the active components of C. alatavicus and potential targets related to prostate cancer, thus providing valuable biological resources for future drug research and development.

Keywords:  Crocus; molecular docking; network pharmacology; prostate cancer

DOI:  https://doi.org/10.3390/ijms26083533