bims-meproc 2025-03-02 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–03–02
seven papers selected by
Grigor Varuzhanyan, UCLA

Hypoxia-Induced VGF Promotes Cell Migration and Invasion in Prostate Cancer via the PI3K/Akt Axis.
Integrated Bioinformatic Analyses Reveal Thioredoxin as a Putative Marker of Cancer Stem Cells and Prognosis in Prostate Cancer.
Integrated Pharmacogenetic Signature for the Prediction of Prostatic Neoplasms in Men With Metabolic Disorders.
Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer.
SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance.
RhoB regulates prostate cancer cell proliferation and docetaxel sensitivity via the PI3K-AKT signaling pathway.
RELATIONSHIP BETWEEN PURINERGIC SIGNALLING AND OXIDATIVE STRESS IN PROSTATE CANCER: PERSPECTIVES FOR FUTURE THERAPY.

Front Biosci (Landmark Ed). 2025 Feb 20. 30(2): 25522

Hypoxia-Induced VGF Promotes Cell Migration and Invasion in Prostate Cancer via the PI3K/Akt Axis.

Leilei Wang, Ting Zhang, Yanning Qian, Yingying Wu, Ting Li, Yongbo Zheng, Chunli Luo, Xiaohou Wu, Tingmei Chen, Liping Ou.

   BACKGROUND: Metastasis is a major cause of prostate cancer (PCa)-related deaths in men. Recent studies have indicated that VGF nerve growth factor inducible (VGF) affects tumor invasion and metastasis. The present study investigated whether VGF is abnormally expressed in PCa and affects PCa progression and investigated the specific regulatory mechanisms by which VGF affects PCa invasion and metastasis.
METHODS: The sh- hypoxia-inducible factor1 alpha (HIF-1α) plasmid was transfected into human cell lines 22Rv1 and C4-2 to create cell lines with stable low expression and overexpression of VGF. Quantitative PCR (qPCR) was performed to detect VGF mRNA. Western blot was performed to detect invasive migration-related proteins. Akt activator SC79 (4 μg/mL) was added. After adding docetaxel (4 nM) to cells transfected with sh-NC and sh-VGF, the capacity of the cells to migrate invasively was assessed using the Transwell and scratch assays. Nude mice were injected with cells stably transfected with sh-NC or sh-VGF and the metastasis of the cancer cells was detected by live imaging and HE staining after the injection of docetaxel (10 mg/kg).
RESULTS: Abnormal levels of VGF in PCa tissue and plasma samples were detected, and VGF knockdown suppressed PCa metastasis. VGF was also shown to affect the invasion and metastasis of PCa cells via PI3K/Akt signaling. VGF knockdown limited PCa metastasis and the inhibitory impact was higher when paired with docetaxel (p < 0.001). After hypoxia induction, both the mRNA and protein levels of VGF and HIF-1α increased, which is associated with a poor prognosis for PCa.
CONCLUSION: By stimulating the PI3K/Akt pathway, VGF encourages the invasive metastasis of PCa. As a result, targeting VGF may be a potential treatment approach for metastatic PCa therapy.

Keywords:  PI3K/Akt; VGF; metastasis; prostate cancer

DOI:  https://doi.org/10.31083/FBL25522
Cancer Inform. 2025 ;24 11769351251319872

Integrated Bioinformatic Analyses Reveal Thioredoxin as a Putative Marker of Cancer Stem Cells and Prognosis in Prostate Cancer.

Shigeru Sugiki, Tetsuhiro Horie, Kenshiro Kunii, Takuya Sakamoto, Yuka Nakamura, Ippei Chikazawa, Nobuyo Morita, Yasuhito Ishigaki, Katsuhito Miyazawa.

   Objectives: Prostate cancer stem cells (CSCs) play an important role in cancer cell survival, proliferation, metastasis, and recurrence; thus, removing CSCs is important for complete cancer removal. However, the mechanisms underlying CSC functions remain largely unknown, making it difficult to develop new anticancer drugs targeting CSCs. Herein, we aimed to identify novel factors that regulate stemness and predict prognosis.
Methods: We reanalyzed 2 single-cell RNA sequencing data of prostate cancer (PCa) tissues using Seurat. We used gene set enrichment analysis (GSEA) to estimate CSCs and identified common upregulated genes in CSCs between these datasets. To investigate whether its expression levels change over CSC differentiation, we performed a trajectory analysis using monocle 3. In addition, GSEA helped us understand how the identified genes regulate stemness. Finally, to assess their clinical significance, we used the Cancer Genome Atlas database to evaluate their impact on prognosis.
Results: The expression of thioredoxin (TXN), a redox enzyme, was approximately 1.2 times higher in prostate CSCs than in PCa cells (P < 1 × 10-10), and TXN expression decreased over CSC differentiation. In addition, GSEA suggested that intracellular signaling pathways, including MYC, may be involved in stemness regulation by TXN. Furthermore, TXN expression correlated with poor prognosis (P < .05) in PCa patients with high stemness.
Conclusions: Despite the limited sample size in our study and the need for further in vitro and in vivo experiments to demonstrate whether TXN functionally regulates prostate CSCs, our findings suggest that TXN may serve as a novel therapeutic target against CSCs. Moreover, TXN expression in CSCs could be a useful marker for predicting the prognosis of PCa patients.

Keywords:  Bioinformatics; MYC; Prostate cancer stem cell; Single-cell RNA sequencing; Thioredoxin

DOI:  https://doi.org/10.1177/11769351251319872
Cancer Genomics Proteomics. 2025 Mar-Apr;22(2):22(2): 285-305

Integrated Pharmacogenetic Signature for the Prediction of Prostatic Neoplasms in Men With Metabolic Disorders.

Maria Pagoni, Vasileios L Zogopoulos, Stavros Kontogiannis, Annia Tsolakou, Vassilios Zoumpourlis, George Th Tsangaris, Eleftherios Fokaefs, Ioannis Michalopoulos, Aristidis M Tsatsakis, Nikolaos Drakoulis.

   BACKGROUND/AIM: Oncogenic processes are delineated by metabolic dysregulation. Drug likeness is pharmacokinetically tested through the CYP450 enzymatic system, whose genetic aberrations under epigenetic stress could shift male organisms into prostate cancer pathways. Our objective was to predict the susceptibility to prostate neoplasia, focused on benign prostatic hyperplasia (BPH) and prostate cancer (PCa), based on the pharmacoepigenetic and the metabolic profile of Caucasians.
MATERIALS AND METHODS: Two independent cohorts of 47,389 individuals in total were assessed to find risk associations of CYP450 genes with prostatic neoplasia. The metabolic profile of the first cohort was statistically evaluated and frequencies of absorption-distribution-metabolism-excretion-toxicity (ADMET) properties were calculated. Prediction of miRNA pharmacoepigenetic targeting was performed.
RESULTS: We found that prostate cancer and benign prostatic hyperplasia patients of the first cohort shared common cardiometabolic trends. Drug classes C08CA, C09AA, C09CA, C10AA, C10AX of the cardiovascular, and G04CA, G04CB of the genitourinary systems, were associated with increased prostate cancer risk, while C03CA and N06AB of the cardiovascular and nervous systems were associated with low-risk for PCa. CYP3A4*1B was the most related pharmacogenetic polymorphism associated with prostate cancer susceptibility. miRNA-200c-3p and miRNA-27b-3p seem to be associated with CYP3A4 targeting and prostate cancer predisposition. Metabolomic analysis indicated that 11β-OHT, 2β-OHT, 15β-OHT, 2α-OHT and 6β-OHT had a high risk, and 16α-OHT, and 16β-OHT had an intermediate disease-risk.
CONCLUSION: These findings constitute a novel integrated signature for prostate cancer susceptibility. Further studies are required to assess their predictive value more fully.

Keywords:  BPH; CYP3A4; FoxO signaling pathway; PCa; Pharmacogenetics; diabetes; dislipidemia; epigenetics; estrogen signaling pathway; hypertension; metabolomics; miRNAs; p53 signaling pathway; prostatic neoplasia; steroid hormone pathway

DOI:  https://doi.org/10.21873/cgp.20502
Mol Oncol. 2025 Feb 26.

Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer.

Retheesh S Thankan, Elizabeth Thomas, Mehari M Weldemariam, Puranik Purushottamachar, Weiliang Huang, Maureen A Kane, Yuji Zhang, Nicholas Ambulos, Bi-Dar Wang, David Weber, Vincent C O Njar.

  Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role in PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels and increased PCa risk and severity. Inhibition of CHOL biosynthesis at different steps, including lanosterol synthase (LSS), has shown significant efficacy against both hormone-dependent and castration-resistant PCa. Earlier, we reported proteasomal degradation of androgen receptor (AR)/AR-Vs and Mnk1/2 as the primary mechanisms of action of VNPP433-3β in inhibiting PCa cell proliferation and tumor growth. Through thermal proteome profiling, comparative proteomics and cellular thermal shift assay, we identified VNPP433-3β's ancillary effect of lowering CHOL by binding to LSS and lanosterol 14-alpha demethylase, potentially inhibiting CHOL biosynthesis in PCa cells and tumors. Additionally, in conjunction with our previously reported transcriptome analysis, proteomics reveals that VNPP433-3β modulated upstream regulators and pathways critical for PCa stem cell maintenance and recurrence. The inhibition of CHOL biosynthesis by VNPP433-3β reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single-agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433-3β's therapeutic potential.

Keywords:  CYP51A1; cholesterol; lanosterol synthase; next‐generation galeterone analog; prostate cancer; thermal proteome profiling

DOI:  https://doi.org/10.1002/1878-0261.70009
Cell Death Discov. 2025 Feb 23. 11(1): 75

SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance.

Guojiang Wei, Ying Huang, Wenya Li, Yuxin Xie, Deyi Zhang, Yuanjie Niu, Yang Zhao.

Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.

DOI: https://doi.org/10.1038/s41420-025-02354-7
BMC Cancer. 2025 Feb 26. 25(1): 354

RhoB regulates prostate cancer cell proliferation and docetaxel sensitivity via the PI3K-AKT signaling pathway.

Tiantian Sheng, Hang Su, Lu Yao, Zhen Qu, Hui Liu, Wenjuan Shao, Xiangyu Zhang.

  Docetaxel is a widely used first-line treatment for castration-resistant prostate cancer (CRPC). RhoB, a member of the Rho GTPase family, plays a major role in prostate cancer metastasis by modulating the PI3K-AKT signaling pathway. It is crucial in regulating cytoskeletal reassembly, cell migration, focal adhesion (FA) dynamics. To investigate RhoB's function in prostate cancer, CRISPR/Cas9 gene editing technique was utilized to knock out the RhoB gene in prostate cancer cells. Successful gene editing was confirmed by using T7 endonuclease I (T7EI) assays and Sanger sequencing. Knocking out RhoB enhanced epithelial-mesenchymal transition (EMT) and decreased the IC50 value of docetaxel in RhoB-knockout PC-3 cells. This suggests increased sensitivity to docetaxel. Furthermore, RhoB knockout prompted the migration and invasion of prostate cancer cells, effects that were reversed upon RhoB overexpression. Interestingly, RhoB status did not significantly influence the cell cycle of prostate cancer cells. RNA sequencing of PC-3 cells with either overexpressed or knock-out RhoB revealed that RhoB regulates pathways involved in FA, ECM receptor interaction, and PI3K-AKT signaling. These pathways directly influence the EMT process, cell migration, and invasion in prostate cancer cells. Notably, RhoB overexpression activated PI3K-AKT signaling when PC-3 cells were treated with low concentration of DTXL (50 nM, 72 h). This activation reduced DTXL's cytotoxicity, suggesting may confer chemoresistance via PI3K-AKT pathway activation.

Keywords:  CRISPR/Cas9; Docetaxel; Prostate cancer; RNA-Seq; RhoB

DOI:  https://doi.org/10.1186/s12885-025-13762-4
Crit Rev Oncol Hematol. 2025 Feb 25. pii: S1040-8428(25)00063-0. [Epub ahead of print] 104675

RELATIONSHIP BETWEEN PURINERGIC SIGNALLING AND OXIDATIVE STRESS IN PROSTATE CANCER: PERSPECTIVES FOR FUTURE THERAPY.

Rafael Zatti Rossetto, Sarah Franco Vieira DE Oliveira Maciel, Andréia Machado Cardoso.

  Prostate cancer (PCa) is a complex and lethal disease in men, influenced by risk factors such as age, heredity, and lifestyle. This article reviews the roles of purinergic signaling and reactive species in PCa progression. The purinergic system involves signaling molecules, such as ATP and adenosine, specific receptors (P1 and P2), and catalytic enzymes (for example, CD39 and CD73), whose alterations contribute to cell proliferation, angiogenesis, and immune evasion. The purinergic receptors P2X7 and P2X4 modulate the prostate tumor microenvironment (TME), impacting hypoxia, apoptosis, and inflammatory pathways. Reactive oxygen species (ROS) and nitrogen species (RNS) also play crucial roles. At elevated levels, they lead to oxidative damage to DNA and mitochondria, promoting genetic instability and uncontrolled cell proliferation. These species interact with the purinergic signaling pathway, with enzymes like CD39 and CD73 playing dual roles: degrading extracellular ATP to generate immunosuppressive adenosine while simultaneously protecting against oxidative damage. This review emphasizes the dynamic interplay between inflammatory and immunosuppressive signals within the TME, mediated by ATP, ROS, and their signaling cascades. This balance determines whether the environment supports tumor progression or regression. Targeting these mechanisms through innovative therapies, including receptor inhibitors and ROS modulation, presents promising avenues for PCa treatment. Understanding the intricate roles of purinergic signaling and reactive species provides valuable insights into potential therapeutic strategies to combat PCa.

Keywords:  Adenosine Triphosphate (ATP); Immune Evasion; Prostate Cancer; Purinergic Signaling; Reactive Oxygen Species (ROS); Tumor Microenvironment (TME)

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104675