bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–03–09
six papers selected by
Grigor Varuzhanyan, UCLA
  1. Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.
  2. EphB4-ephrin-B2 are targets in castration resistant prostate cancer.
  3. Enhancing prostate cancer cells' sensitivity to flutamide by resveratrol: An in-vitro study.
  4. Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.
  5. A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells.
  6. Targeting obesity, metabolic syndrome, and prostate cancer: GLP-1 agonists as emerging therapeutic agents.
  1. Cell Death Dis. 2025 Mar 05. 16(1): 154
    Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.
    Taiyang Ma, Wenjuan Xie, Zhenyu Xu, Weijie Gao, Jianfu Zhou, Yuliang Wang, Franky Leung Chan.
      Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.
    DOI:  https://doi.org/10.1038/s41419-025-07460-z
  2. Br J Cancer. 2025 Mar 05.
    EphB4-ephrin-B2 are targets in castration resistant prostate cancer.
    Grace Xiuqing Li, Binyun Ma, Shaobing Zhang, Ren Liu, Imran N Siddiqi, Akash Sali, Anthony El-Khoueiry, Mitchell Gross, Bodour Salhia, Sarmad Sadeghi, Parkash S Gill.
       BACKGROUND: PI3K pathway activation is a common and early event in prostate cancer, from loss of function mutations in PTEN, or activating mutations in PIK3Ca or AKT leading to constitutive activation, induction of growth factor-receptors kinase EphB4 and its ligand ephrin-B2. We hypothesized that induction of EphB4 is an early event required for tumor initiation. Secondly, we hypothesized that EphB4 remains relevant when prostate cancer becomes androgen independent.
    METHODS: Genetic mouse model of conditional PTEN deletion in prostate epithelium induces tumor in all mice. We tested this model against EPHB4 wild type and deleted in prostate epithelium. This allowed us to test its role in tumor initiation. We also tested an orthogonal approach by using decoy soluble EphB4 to block bidirectional signaling resulting from EphB4-ephrin-B2 interaction. Role of EphB4-ephrin-B2 in androgen deprived mice was tested for role in refractory cancer model.
    RESULTS: PTEN deletion induces EphB4 and ephrin-B2 in prostate cancer which was substantially reduced when EPHB4 is deleted in the same prostate epithelial cells. sEphB4-alb fusion protein with improved pharmacokinetics similarly inhibited tumor formation, thus establishing the role in tumor initiation. sEphB4-alb retained the efficacy in castration resistant androgen independent prostate cancer. We have thus observed that induction of EphB4 is required for the initiation of prostate cancer in PTEN null mouse and that signaling downstream from EphB4 is required in androgen deprivation and thus castration resistant prostate cancer. Pharmacological inhibition of EphB4 pathway reproduced the results. Targeting EphB4 should be tested in prostate cancer especially those resistant to androgen deprivation therapy.
    CONCLUSIONS: EphB4 and ephrin-B2 receptor ligand pair is induced in PTEN null prostate cancer, which significantly contributes to the tumor initiation. Secondly, EphB4-ephrin-B2 pathway continue to promote tumor progression even in androgen deprivation and thus hormone refractory tumor. EphB4-ephrin-B2 may be candidates for precision medicine with biomarker-based patient selection with and without concurrent standard of care.
    DOI:  https://doi.org/10.1038/s41416-025-02942-5
  3. Tissue Cell. 2025 Feb 21. pii: S0040-8166(25)00087-4. [Epub ahead of print]94 102807
    Enhancing prostate cancer cells' sensitivity to flutamide by resveratrol: An in-vitro study.
    Seyedeh Fatemeh Hosseini, Seyed Reza Yahyazadeh, Akram Mirzaei, Rahil Mashhadi, Helia Azodian Ghajar, Diana Taheri, Seyed Mohammad Kazem Aghamir.
       BACKGROUND: As the most common cancer in men, and its progression poses a significant challenge. New and effective treatment strategies are needed to improve outcomes for patients with prostate cancer. This study examined if resveratrol, a natural substance, could improve prostate cancer cell lines' response to flutamide, a standard antiandrogenic treatment for untreated prostate cancer, while minimizing adverse effects.
    METHOD: MTT assay was used to quantify resveratrol and flutamide IC50 values, Annexin-V/PI staining for apoptosis, PI staining for DNA cell cycle, and real-time PCR for BAX, BCL-2, VEGFC, HIF-1α, Snail1, E-Cadherin, and KLK3 mRNA levels Scratch-wound, colony-forming, and Hoechst staining analyzed cell migration, proliferation, and nucleus morphology. Spheroid creation in 3D was also considered. All tests used LNCaP, DU145, and PC3 prostate cancer cell lines at various stages.
    RESULTS: Resveratrol, when combined with flutamide, can reduce malignant cell migration, colony formation, and proliferation and promote apoptosis in prostate cancer cell lines. Even in androgen-unresponsive cell lines (DU145 and PC3), it may benefit flutamide prostate cancer treatment. Apoptosis genes (BAX) were upregulated in LNCaP, DU145, and PC3 cancer cell lines when administered alone or with flutamide. Additionally, flutamide might significantly lower BCL-2 levels in PC3 cells. When combined with flutamide, resveratrol increased apoptosis and altered the expression of genes involved in angiogenesis (VEGFC), epithelial-mesenchymal transition (EMT, Snail1 and E-Cadherin), and prostate cancer biomarker (KLK3) in prostate cancer cell lines.
    CONCLUSION: Resveratrol reduced the dose of flutamide in the treatment of prostate cancer cell lines (LNCaP, DU145, and PC3) and improved its side effects, as well as increasing the sensitivity of cells to flutamide treatment.
    Keywords:  Androgen receptor; Flutamide; Prostate cancer; Resveratrol
    DOI:  https://doi.org/10.1016/j.tice.2025.102807
  4. bioRxiv. 2025 Feb 17. pii: 2025.02.12.637904. [Epub ahead of print]
    Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.
    Shan Li, Kai Song, Huiyun Sun, Yong Tao, Arthur Huang, Vipul Bhatia, Brian Hanratty, Radhika A Patel, Henry W Long, Colm Morrissey, Michael C Haffner, Peter S Nelson, Thomas G Graeber, John K Lee.
      Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.
    DOI:  https://doi.org/10.1101/2025.02.12.637904
  5. Oncogene. 2025 Mar 06.
    A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells.
    Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Yubing Ye, Yongming Fu, Yuchong Peng, Ruizheng Tan, Li Fang, Haoran Suo, Xuli Qi, Bowen Yuan, Yingxue Gao, Youhong Liu, Xiong Li.
      Prostate cancer (PCa) is an androgen-dependent malignancy, with HSP90 and HSP70 serving as classical molecular chaperones that maintain androgen receptor (AR) protein stability and regulate its transcriptional activation. Surprisingly, our study identified TOMM20, a mitochondrial outer membrane protein, as a potential molecular chaperone with similar roles to HSP90/HSP70. We found that TOMM20 expression is elevated in PCa tissues and cell lines and positively correlates with AR levels. RNA-seq analysis revealed that TOMM20 knockdown significantly reduced the mRNA levels of AR-regulated genes. Additionally, the protein level of KLK3 (PSA) decreased, and AR binding to the androgen response element (ARE) of the KLK3 promoter was diminished following TOMM20 knockdown, leading to decreased KLK3 gene transcription. Furthermore, TOMM20 depletion reduced both cytoplasmic and nuclear AR protein levels and facilitated AR degradation via an E3 ubiquitin ligase SKP2-mediated ubiquitin-proteasome pathway, independent of heat shock proteins (HSPs). To our knowledge, this is the first report demonstrating that TOMM20, a mitochondrial outer translocase protein, stabilizes AR protein and enhances its transcriptional activity, while its knockdown promotes AR degradation through the SKP2-mediated ubiquitin-proteasome pathway. These findings suggest that TOMM20 may serve as a potential biomarker for PCa progression and a promising therapeutic target for drug development.
    DOI:  https://doi.org/10.1038/s41388-025-03328-w
  6. Discov Oncol. 2025 Mar 01. 16(1): 258
    Targeting obesity, metabolic syndrome, and prostate cancer: GLP-1 agonists as emerging therapeutic agents.
    Azura Murphy, Ritis Kumar Shyanti, Manoj Mishra.
      Prostate cancer (PCa) is known as the second most common cancer and has one of the highest incidences among male cancers in the United States. In addition, obesity and metabolic syndrome are a rising and continuous issue in the United States, with 41.9% of individuals as obese. The importance of highlighting these figures is the possibility of PCa having a progressive relationship with obesity and metabolic syndromes. The drugs developed for treating obesity and diabetes pose an exciting possibility of therapeutic application for cancer in efforts to relieve the population's rising numbers. Although this connection has not been established in detail, there are some PCa key biomarkers, and their interactions with metabolic products found in obese, diabetic, and PCa patients can provide good starting points for further investigation. One of the significant links between PCa, obesity, and metabolic disease may be due to insulin metabolism. A downstream target identified that could be the link between PCa, metabolic syndromes, and obesity is the forkhead box C2 (FOXC2). FOXC2 has been known to inhibit some insulin-resistant genes and cause the proliferation of PCa. The relationships of FOXC2, insulin resistance, and GLP-1 receptor agonists as potential therapeutic applications have not been thoroughly explored. This review covers a broad relationship of PCa, obesity, metabolic syndromes, possible drugs, and therapeutic targets.
    Keywords:  FOXC2; GLP-1; Insulin resistance; Metabolic syndrome; Obesity; Prostate cancer
    DOI:  https://doi.org/10.1007/s12672-025-01878-9
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