bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–03–23
six papers selected by
Grigor Varuzhanyan, UCLA
  1. C1QBP Promotes Prostate Cancer Progression and Lipid Accumulation by Negatively Regulating ALDH9A1.
  2. Fatty acid metabolism related gene MECR contributes to the progression of prostate cancer.
  3. Metabolic Reprogramming into a Glycolysis Phenotype Induced by Extracellular Vesicles Derived from Prostate Cancer Cells.
  4. Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.
  5. The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and risk of prostate cancer: a retrospective study.
  6. Aberrant expression of multiple γ-glutamyltransferases is associated with tumor progression and patient outcome in prostate cancers.
  1. Mol Carcinog. 2025 Mar 18.
    C1QBP Promotes Prostate Cancer Progression and Lipid Accumulation by Negatively Regulating ALDH9A1.
    Xinyu Liu, Jiaxin Li, Runxuan Du, Qiufang Qiao, Shuang Liu, Zhihao Bo, Ruibing Chen, Yihan Dong, Xuesong Xiao, Yuejing Pan, Huamao Jiang, Rui Wang, Yong Wang, Dan Yue.
      Prostate cancer (PCa) relies heavily on lipid metabolism for energy acquisition, and lipid metabolic reprogramming plays a crucial role in its progression. Here, we utilized publicly available PCa databases and immunohistochemistry to evaluate C1QBP expression in PCa. We found that C1QBP is highly expressed in PCa, potentially due to promoter hypomethylation. Functional assays showed that C1QBP promotes cell proliferation, migration, and lipid accumulation in PCa cells. We identified differentially expressed proteins associated with C1QBP by using liquid chromatography-tandem mass spectrometry. Functional enrichment analysis revealed that C1QBP affects lipid metabolism and negatively regulates the lipid metabolism-related molecule ALDH9A1. Furthermore, ALDH9A1 intervention rescued the tumor suppression and lipid reduction caused by C1QBP knockdown. RNA sequencing (RNA-seq) was performed to explore C1QBP regulatory pathways at the mRNA level, revealing that C1QBP also affects the MAPK and p53 pathways, as well as the expression of lipid metabolism-related molecules. In conclusion, these findings suggest that C1QBP influences PCa progression and lipid deposition by regulating ALDH9A1, while other potential mechanisms may also be involved, indicating that C1QBP is a promising target for PCa treatment.
    Keywords:  ALDH9A1; C1QBP; lipid metabolism; prostate cancer
    DOI:  https://doi.org/10.1002/mc.23904
  2. Cancer Cell Int. 2025 Mar 19. 25(1): 105
    Fatty acid metabolism related gene MECR contributes to the progression of prostate cancer.
    Yifan Liu, Lilin Wan, Yuxuan Chen, Ruixin Zhang, Yi Xia, Ming Chen, Xiang Huang, Ruiji Liu.
       BACKGROUND: Prostate cancer (PCa) is the most common urological malignancy and second only to lung cancer in incidence among men. Its prognosis varies widely due to its heterogeneity. Research indicates that fatty acid metabolism may play a role in tumor development.
    METHODS: The gene expression profiles of PCa cell lines (GSE6919) in GEO database were analyzed to identify differentially expressed genes and their significance in relation to progression-free interval. The R package was employed to assess overall survival significance and clinicopathological features. The study investigated the effects of gene mutations and methylation on PCa and their correlation with immune cell infiltration in the tumor microenvironment, utilizing cBioPortal and UALCAN resources. TIMER was used in the TCGA project to compare the expression of MECR in tumours and in adjacent normal tissue for different tumours or for specific tumour subtypes. Furthermore, we examined the impact of hub genes on PCa progression through RT qPCR, immunohistochemistry, and cellular assays.
    RESULTS: The MECR gene, which plays a role in fatty acid metabolism, has been implicated in the development and progression of PCa. Its expression levels are significantly associated with clinical features, survival outcomes, and prognosis in PCa. Comprehensive analyses of MECR mutations and methylation levels further underscore its involvement in the progression of prostate cancer. Additionally, MECR is closely associated with the immune microenvironment and immune cell infiltration in PCa. Furthermore, the in vitro and in vivo data indicated that MECR plays a role in PCa proliferation, migration, and invasion.
    CONCLUSION: MECR has significant potential for research and application in the assessment of PCa prognosis and the regulation of the immune microenvironment.
    Keywords:  Fatty acid metabolism; Immune microenvironment; MECR; Prostate cancer
    DOI:  https://doi.org/10.1186/s12935-025-03738-6
  3. Mol Cell Proteomics. 2025 Mar 13. pii: S1535-9476(25)00042-8. [Epub ahead of print] 100944
    Metabolic Reprogramming into a Glycolysis Phenotype Induced by Extracellular Vesicles Derived from Prostate Cancer Cells.
    Yoon-Jin Lee, Chul Won Seo, Shinwon Chae, Chang Yeol Lee, Sang Soo Kim, Yoon-Hee Shin, Hyun-Mee Park, Yong Song Gho, Seongho Ryu, Sang-Han Lee, Dongsic Choi.
      Most cancer cells adopt a less efficient metabolic process of aerobic glycolysis with high level of glucose uptake followed by lactic acid production, known as the Warburg effect. This phenotypic transition enables cancer cells to achieve increased cellular survival and proliferation in a harsh low-oxygen tumor microenvironment. Also, the resulting acidic microenvironment causes inactivation of the immune system such as T-cell impairment that favors escape by immune surveillance. While lots of studies have revealed that tumor-derived EVs can deliver parental materials to adjacent cells and contribute to oncogenic reprogramming, their functionality in energy metabolism is not well addressed. In this study, we established prostate cancer cells PC3-AcT resistant to cellular death in an acidic culture medium driven by lactic acid. Quantitative proteomics between EVs derived from PC-3 and PC-3AcT cells identified 935 confident EV proteins. According to cellular adaptation to lactic acidosis, we revealed 159 regulated EV proteins related to energy metabolism, cellular shape, and extracellular matrix. These EVs contained a high abundance of glycolytic enzymes. In particular, PC-3AcT EVs were enriched with apolipoproteins including apolipoprotein B100 (APOB). APOB on PC-3AcT EVs could facilitate their endocytic uptake depending on low density lipoprotein receptor of recipient PC-3 cells, encouraging increases of cellular proliferation and survival in acidic culture media via increased activity and expression of hexokinases and phosphofructokinase. The activation of recipient PC-3 cells can increase glucose consumption and ATP generation, representing an acquired metabolic reprogramming into the Warburg phenotype. Our study first revealed that EVs derived from prostate cancer cells could contribute to energy metabolic reprogramming and that the acquired metabolic phenotypic transition of recipient cells could favor cellular survival in tumor microenvironment.
    DOI:  https://doi.org/10.1016/j.mcpro.2025.100944
  4. J Transl Med. 2025 Mar 18. 23(1): 347
    Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer.
    Yuqi Guo, Zhiyuan Zhang, Lintao Dong, Xinyi Shi, Xiaohan Li, Mingxiu Luo, Yajuan Fu, Yujing Gao.
       BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18-24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.
    METHODS: In this study, we investigated the role of Wnt5a, a member of the Wnt family, in CRPC. Tumor tissues from CRPC patients were analyzed to assess the expression levels of Wnt5a. Prostate cancer cells were used to examine the impact of Wnt5a on androgen-dependent and -independent growth, as well as sensitivity to bicalutamide. RNA-seq analysis, qRT-PCR, intracellular cholesterol content and the activation of the androgen receptor (AR) signaling pathway were evaluated to elucidate the mechanistic role of Wnt5a in CRPC progression. Drug target Mendelian randomization analysis was performed to investigate the effect of PCSK9 inhibitor on prostate cancer.
    RESULTS: Our study revealed a significant overexpression of Wnt5a in tissues from CRPC tumors. Wnt5a was found to enhance both androgen-dependent and -independent growth in prostate cancer cells while reducing their sensitivity to bicalutamide. Mechanistically, Wnt5a was shown to upregulate intracellular free cholesterol content and activate the AR signaling pathway, contributing to hormone therapy resistance in CRPC. PCSK9 inhibitor significantly reduced the risk of PCa.
    CONCLUSIONS: The findings of this study highlight a novel molecular mechanism underlying endocrine therapy resistance in CRPC mediated by Wnt5a. Targeting Wnt5a or reducing cholesterol level would be a promising therapeutic strategy for the treatment of CRPC, providing new insights into potential avenues for combating this challenging form of prostate cancer.
    Keywords:  Androgen receptor signaling; Castration resistance; Cholesterol; Prostate cancer
    DOI:  https://doi.org/10.1186/s12967-025-06322-8
  5. PeerJ. 2025 ;13 e19065
    The association between non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and risk of prostate cancer: a retrospective study.
    Ke Bu, Jinru Wang, Xiaojie Zheng, Kaige Zhang, Duolao Wang, Hengqing An, Ning Tao.
       Background: Prostate cancer is one of the most frequent malignancies in the world, with significant morbidity and death rates. Identifying novel biomarkers is critical to reducing morbidity and mortality from the illness today. Although lipids have been linked to an increased risk of prostate cancer, it is unclear if the non-high-density lipoprotein cholesterol (NHDL-C) to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) is related to prostate cancer. Therefore, we assessed the relationship between NHHR and prostate cancer risk.
    Methods: This study comprised 1,718 individuals who attended the First Affiliated Hospital of Xinjiang Medical University between March 2020 and March 2024. A pathological examination of a prostate puncture biopsy was utilized to confirm the diagnosis of prostate cancer. The study collected information on participants' clinical and laboratory examinations, used propensity score matching to eliminate potential confounders, and analyzed the relationship between NHHR and prostate cancer, using logistic regression models combined with restricted cubic spline (RCS) and receiver operating characteristic (ROC) curve. Furthermore, sensitivity analyses were undertaken to assess the robustness of the results.
    Results: (1) There were statistically significant differences in neutrophils, erythrocytes, triglycerides, alkaline phosphatase, and NHHR between the two groups; (2) after adjusting for all covariates, logistic regression revealed a negative association between NHHR and prostate cancer (0.91 (0.83∼0.99), P = 0.028). Participants in the second quartile had a significantly lower risk of prostate cancer after comprehensive adjustment (0.69 (0.50∼0.96), P = 0.026); (3) the restrictive cubic spline curve shows a non-linear relationship between NHHR and prostate cancer risk, with a turning point of 1.824; (4) the results of the ROC curve showed that the NHHR had an area under the curve (AUC) of 0.73; the results of the decision curve suggested that the model was able to provide a high benefit value for patients, with a threshold range of approximately 0.01-0.98 and a maximum net benefit of 0.52, and the calibration curve demonstrated that the model was accurate and reliable.
    Conclusions: There is a non-linear dose-response relationship between NHHR and prostate cancer risk, which may be associated with a reduced risk of prostate cancer. The finding can be used to detect high-risk groups and prevent prostate cancer.
    Keywords:  Non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR); Prostate cancer; Total cholesterol
    DOI:  https://doi.org/10.7717/peerj.19065
  6. Front Oncol. 2025 ;15 1518636
    Aberrant expression of multiple γ-glutamyltransferases is associated with tumor progression and patient outcome in prostate cancers.
    Wencong Jiang, Wang Liu, Jiang Zhao, Zhijian Xu, Ming Xi, Xiangwei Wang, Benyi Li.
       Introduction: The human gamma-glutamyltransferase (GGT) is a membrane-bound extracellular glycoprotein with an enzymatic activity that cleaves gamma-glutamyl peptide bonds in glutathione and other peptides and transfers the gamma-glutamyl moiety to acceptors. It has been shown aberrant expression of GGT proteins in human cancers while their expression profiles in prostate cancers are not reported.
    Methods: In this study, we analyzed the expression profiles of all protein-coding GGT genes using the TCGA-PRAD RNA-seq dataset derived from primary prostate cancers. GGT family gene expression profiles were also analyzed using the SU2C/PCF RNAseq dataset derived from aggressive late-stage prostate cancer patients. Androgen modulation of GGT family gene expression was analyzed using multiple NCBI/GEO datasets.
    Results: Our results showed that prostate tissues expressed four major isoforms of GGT family genes (GGT1/5/6/7), of which GGT1 expression was upregulated but GGT6/GGT7 expression was downregulated in cancer tissues compared to benign tissues. However, GGT5 expression was increased along with tumor stage progression and associated with worse progression-free survival. GGT6 expression exhibited a superb AUC value in prostate cancer diagnosis and was associated with favorable progression-free survival. GGT1 expression was highly increased but GGT6/GGT7 expression was largely reduced in ERG-fusion-positive cases. In CRPC tumors, GGT6 expression was suppressed in patients with anti-AR therapies, which was reversed when patients were taken off the treatment. This AR-dependent modulation was confirmed in LNCaP cells and LuCaP35 xenograft models. In addition, compared to CRPC-Adeno tumors, treatment-induced NEPC tumors showed a reduced GGT1 but an elevated GGT7 level, which was in line with higher levels of GGT7 in NEPC H660 cells.
    Conclusion: Our data suggests that GGT6 is a new AR downstream target but GGT7 is a potential NEPC biomarker.
    Keywords:  DNA methylation; GGT family genes; castration-resistance; neuroendocrinal progression; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1518636
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