bims-meproc 2025-05-25 papers

bims-meproc

Biomed News

on Metabolism in Prostate Cancer

Issue of 2025–05–25
nine papers selected by
Grigor Varuzhanyan, UCLA

Delta 4-desaturase sphingolipid 2 enhances prostate cancer stem-like traits through phytoceramide-mediated PI3K-AKT signaling pathway.
The SP1/SNHG16/GLUT1 axis promotes prostate cancer proliferation and invasion by regulating glucose metabolism.
Gnetin C sensitizes darolutamide-resistant prostate cancer cells by targeting NAD+ and energy metabolism.
DHA suppresses hormone-sensitive and castration-resistant prostate cancer growth by decreasing de novo lipogenesis.
6-Shogaol inhibits the cell motility of prostate cancer cells by suppressing the PI3K/AKT/mTOR and Ras/Raf/MAPK pathways with comparable effects to paclitaxel treatment.
Mitochondrial SLC25A10 promotes prostate cancer progression by inhibiting ferritinophagy.
Ketogenesis instigates immune suppression in enzalutamide resistant prostate cancer via OTUD7B β-hydroxybutyrylation.
Knowledge-guided multi-level network modeling with experimental characterization identifies PRKCA as a novel biomarker and tumor suppressor triggering ferroptosis in prostate cancer.
Targeting polyamine metabolism in an ex vivo prostatectomy model.

Carcinogenesis. 2025 May 17. pii: bgaf024. [Epub ahead of print]

Delta 4-desaturase sphingolipid 2 enhances prostate cancer stem-like traits through phytoceramide-mediated PI3K-AKT signaling pathway.

Yuanyuan Luo, Jiachuan Yu, Qi Li, Xiaolin Wang, Xinyu Liu, Guowang Xu, Wangshu Qin.

  Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, metastasis, and recurrence and play a crucial role in androgen deprivation therapy resistance, yet how sphingolipid metabolism promotes CSC maintenance remains exclusive. Here, we conducted gene expression profiling of sphere-derived castration-resistant prostate cancer stem cells (PCSCs) and identified enhanced sphingolipid de novo biosynthesis with upregulated DEGS2 expression in PCSCs. Silencing of DEGS2 significantly suppressed prostate cancer stem-like traits, cell growth, clonogenicity, and metastasis, while ectopic overexpression of DEGS2 showed the opposite effects. Mechanistically, DEGS2-synthesized phytoceramide activates PI3K-AKT signaling pathway to promote cancer stem-like characteristics, and activation of AKT reversed DEGS2-depletion-inhibited cancer stem-like properties. Clinically, prostate cancer tissues expressed higher levels of DEGS2 compared with adjacent normal tissue, and DEGS2 expression exhibits strong correlations with SOX2, CD133 and Snail expression in primary prostate carcinomas. Collectively, our data illustrate that DEGS2 dictates prostate cancer stem-like properties via the PI3K-AKT pathway, and disruption of this pathway provides potential therapeutic strategies for prostate cancer.

Keywords:  AKT; Cancer stem cells; DEGS2; EMT; Proliferation; Prostate cancer

DOI:  https://doi.org/10.1093/carcin/bgaf024
Arch Med Sci. 2025 ;21(2): 638-647

The SP1/SNHG16/GLUT1 axis promotes prostate cancer proliferation and invasion by regulating glucose metabolism.

Hua Huang, Wen Zhang.

   Introduction: The SP1/SNHG16/GLUT1 axis is involved in diverse cancer-related processes. This study was designed to study the role of the SP1/SNHG16/GLUT1 axis in prostate cancer (PCa) via modulation of glucose metabolism.
Material and methods: The expression profile of SNHG16 in PCa tissues was obtained from the online public database GEPIA (http://gepia.cancer-pku.cn/). Human prostate cancer cell lines, PC-3 and DU-145, were used in this study. Real-time qPCR was employed to determine the mRNA expression levels of SNHG16 and GLUT1. To assess cellular proliferation, CCK-8 assays were performed. Cellular invasion was evaluated using Transwell assays, and glycolysis was monitored through glucose uptake, lactate production, and ATP generation measurements.
Results: Analysis of GEPIA2 data revealed upregulation of SNHG16 in PCa tissues and a positive association between GLUT1 (SLC2A1) and SP1/SNHG16 expression in the correlation study. Consistently, SPI and SNHG16 were either overexpressed or knocked down in PCa cells to reveal the role of the SP1/SNHG16/GLUT1 axis. The results demonstrated that PC-3 and DU145 cell proliferation was promoted by the overexpression of either SPI or SNHG16. On the other hand, PC-3 and DU145 cell proliferation was reduced upon knockdown of SP1 or SNHG16. A real-time qPCR study revealed that GLUT1 mRNA was upregulated by SP1/SNHG16 overexpression and downregulated by SP1/SNHG16 knockdown. In PCa cells, overexpression of SNHG16/SP1 resulted in enhanced utilization of glucose, lactose, and ATP production, whereas SNHG16/SP1 knockdown had the reverse effect. Lastly, Transwell assay results showed that overexpression of SNHG16/SP1 promoted, while knockdown of SNHG16/SP1 inhibited, the invasiveness of PC-3 and DU145 PCa cells.
Conclusions: Collectively, the evidence indicates that the SP1/SNHG16/GLUT1 axis regulates proliferation of PCa cells via the glycolytic route and thus may act as a therapeutic target for PCa treatment.

Keywords:  SP1/SNHG16; glucose metabolism; invasion; proliferation; prostate cancer

DOI:  https://doi.org/10.5114/aoms/191153
Biochem Biophys Res Commun. 2025 May 14. pii: S0006-291X(25)00723-5. [Epub ahead of print]770 152009

Gnetin C sensitizes darolutamide-resistant prostate cancer cells by targeting NAD+ and energy metabolism.

Mina Kawai, Tomofumi Saka, Shinya Kawano, Yudai Kudo, Teiko Komori Nomura, Ryo Honda, Yuta Yoshino, Hirohito Kashiwagi, Naohito Abe, Masayoshi Oyama, Akira Ikari, Satoshi Endo.

  Resistance to androgen receptor-targeted therapies, including darolutamide (Dar), remains a major challenge in treating castration-resistant prostate cancer (CRPC). Metabolic adaptations, particularly involving dysregulated NAD+ metabolism and altered energy pathways, have been implicated in therapeutic resistance. In this study, we investigated whether Gnetin C-a resveratrol dimer derived from Gnetum gnemon-could overcome Dar resistance in prostate cancer cells. A recently established Dar-resistant 22Rv1 cell line (Dar-R) exhibited a metabolically quiescent phenotype, characterized by suppressed NAD+ metabolism, a decreased NAD+/NADH ratio, and simultaneous inhibition of both glycolysis and oxidative phosphorylation. Gnetin C demonstrated strong anticancer activity in both parental and Dar-R cells. In Dar-R cells, it downregulated NMNAT2, resulting in intracellular NAD+ depletion, and suppressed key mitochondrial proteins, leading to mitochondrial dysfunction. Gnetin C also downregulated Drp1 and upregulated Mitofusin-2, indicating a role in mitochondrial dynamics, and further inhibited glycolytic enzymes and glycolytic activity. These combined effects contributed to its potent anticancer activity by impairing both mitochondrial and glycolytic energy metabolism. Notably, Gnetin C significantly enhanced Dar sensitivity in Dar-R cells, accompanied by increased production of total and mitochondrial reactive oxygen species and the induction of apoptosis. These findings identify Gnetin C as a promising candidate for overcoming drug resistance in CRPC through metabolic disruption.

Keywords:  Anticancer drug resistance; Darolutamide; Energy metabolism; Gnetin C; NAD(+) metabolism; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbrc.2025.152009
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 May 16. pii: S1388-1981(25)00042-3. [Epub ahead of print] 159634

DHA suppresses hormone-sensitive and castration-resistant prostate cancer growth by decreasing de novo lipogenesis.

G H Tamarindo, C F Ribeiro, S Rodrigues, R M Góes, M Loda.

   OBJECTIVE: De novo lipogenesis (DNL) is associated with prostate cancer (PCa) progression, while fatty acid synthase (FASN) overexpression is a hallmark of DNL. Palmitate, its main product, is a saturated fatty acid that supports PCa growth. Polyunsaturated fatty acids (PUFAs), which can be acquired from the microenvironment, undergo peroxidation more readily and affect membrane fluidity. Docosahexaenoic acid (DHA) is a prototype PUFA omega-3 produced inefficiently in human cells. Its levels are low in PCa cells compared to normal cells. We hypothesize that excess DHA may reprogram lipid metabolism and induce cell growth suppression.
METHODS: Androgen-responsive LNCaP, castration-resistant cells C4-2 and 22Rv1, human PCa castration-resistant organoids, and prostate cancer xenografts were exposed to DHA.
RESULTS: DHA accumulated into lipid droplets as triacylglycerols and cholesterol esters, led to increased phospholipid acyl chain unsaturation and altered phospholipid ratio, a known trigger of endoplasmic reticulum (ER) stress. DHA caused a decrease in sterol regulatory element-binding protein (SREBP) transcriptional program, which, in turn, led to decreased expression of FASN. The subsequent reduction in DNL caused downregulation of the androgen receptor (AR) and its splice variant AR-V7. In addition, β-oxidation was enhanced, and DHA was preferentially oxidized over palmitate. Glucose oxidation also increased in the presence of DHA. Finally, DHA led to ROS overproduction, oxidative damage, and ER stress.
CONCLUSIONS: DHA reduces the growth of hormone-sensitive and castration-resistant PCa both in vitro and in vivo via deregulation of lipid metabolism.

Keywords:  DHA; Omega-3; Prostate cancer;lipids

DOI:  https://doi.org/10.1016/j.bbalip.2025.159634
Food Funct. 2025 May 21.

6-Shogaol inhibits the cell motility of prostate cancer cells by suppressing the PI3K/AKT/mTOR and Ras/Raf/MAPK pathways with comparable effects to paclitaxel treatment.

Pei-Jhen Cai, Sheng-Yi Chen, Yi-Fan Chen, Gow-Chin Yen.

Prostate cancer ranks among the top causes of cancer-related deaths in men, with a substantial number of fatalities occurring in metastatic cases. Although paclitaxel (PTX) is used as a first-line treatment, its effectiveness is hindered by side effects and drug resistance, which complicate the therapy and contribute to the progression of metastasis. Research has shown that phytochemicals can induce cancer cell death and inhibit metastasis without significantly harming normal cells, suggesting a potential alternative strategy for suppressing metastatic prostate cancer. 6-Shogaol (6-S), a pungent constituent of ginger, has been demonstrated to inhibit metastasis in renal cancer cells, human endometrial carcinoma, and lung and breast cancers by downregulating the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways. However, the anti-metastatic effects of 6-S on prostate cancer remain unclear. Accordingly, this study was aimed at investigating how 6-S suppresses the metastatic capacity of human prostate cancer cells PC-3 and DU145. Results showed that 6-S inhibited cell migration and invasion in both cell lines in a dose-dependent manner, and no cytotoxicity was observed in the normal human prostate cell RWPE-1. Mechanistically, 6-S upregulated PTEN and suppressed the activation of the CXCL12/CXCR4, PI3K/AKT/mTOR, and Ras/Raf/MAPK pathways, which in turn affected the expression of transcription factors Snail and Twist, leading to increased E-cadherin levels and reduced expression of N-cadherin, vimentin, MMP-2, and MMP-9. This limited the cell motility and showed comparable effects to paclitaxel treatment. In summary, 6-S demonstrates significant potential against the metastatic characteristics of prostate cancer cells and could serve as a potential candidate for adjuvant therapy after further clinical evaluations.

DOI: https://doi.org/10.1039/d5fo00798d
Cell Death Discov. 2025 May 20. 11(1): 242

Mitochondrial SLC25A10 promotes prostate cancer progression by inhibiting ferritinophagy.

Guopeng Yu, Kailei Chen, Bin Xu, Qi Cao.

Prostate cancer (PCa) is one of the most common malignancies in men worldwide and remains a major cause of cancer-related mortality. Despite advances in early diagnosis and treatment, a significant proportion of patients eventually progress to advanced or treatment-resistant disease, highlighting the urgent need for novel therapeutic targets and strategies. In this study, we systematically analyzed transcriptomic data from The Cancer Genome Atlas (TCGA) and performed Venn analysis to identify genes associated with PCa progression. Among the intersecting candidates, SLC25A10, a mitochondrial carrier protein, emerged as a potential key regulator of ferroptosis. Further expression analyses revealed that SLC25A10 is significantly upregulated in PCa tissues and correlates with poor prognosis. Functional gain- and loss-of-function experiments demonstrated that SLC25A10 promotes tumor cell proliferation, migration, and invasion, while exacerbating mitochondrial dysfunction and impairing autophagic flux. Mechanistically, mass spectrometry and co-immunoprecipitation (Co-IP) assays confirmed a direct interaction between SLC25A10 and P62, implicating this interaction in the suppression of autophagy and the promotion of ferroptotic vulnerability. Moreover, disruption of the SLC25A10/p62/KEAP1/Nrf2 signaling axis reactivated autophagy and inhibited PCa cell growth. Collectively, our findings uncover a novel oncogenic role of SLC25A10 in PCa and suggest that targeting the SLC25A10-mediated regulatory network may offer a promising therapeutic avenue for patients with advanced prostate cancer.

DOI: https://doi.org/10.1038/s41420-025-02528-3
Cancer Lett. 2025 May 18. pii: S0304-3835(25)00375-1. [Epub ahead of print] 217808

Ketogenesis instigates immune suppression in enzalutamide resistant prostate cancer via OTUD7B β-hydroxybutyrylation.

Haoran Jiang, Yuan Zeng, Weiqiang Ning, Junkai Hong, Moyang Zhu, Ping Li, Fangdie Ye, Zhifa Chen, Haoran Chen, Wei Chen, Gang Li, Hang Huang.

Next-generation androgen receptor inhibitors are the primary treatment for metastatic prostate cancer. Unfortunately, the majority of patients rapidly develop resistance. Resistance to enzalutamide has been linked to the emergence of an immunosuppressive tumor, although the underlying mechanisms remain poorly understood. In this study, we observed a marked overexpression of enzymes involved in the ketogenic pathway in enzalutamide-induced castration-resistant prostate cancer, which contributed to immune desertification and resistance to immunotherapy. Mechanistically, upregulation of the ketogenic pathway led to the accumulation of β-hydroxybutyrate, which promoted β-hydroxybutyrylation of the cell cycle-regulated deubiquitinase OTUD7B at lysine 511. This modification impaired the degradation of APC/C substrates, resulting in a subsequent reduction in cytoplasmic double-stranded DNA accumulation, thereby attenuating cGAS-STING activation and interferon expression. These findings shed light on the metabolic adaptations and immune escape driven by androgen receptor signaling inhibitors, potentially informing the development of more effective and durable therapeutic approaches in the near future.

DOI: https://doi.org/10.1016/j.canlet.2025.217808
Brief Bioinform. 2025 May 01. pii: bbaf220. [Epub ahead of print]26(3):

Knowledge-guided multi-level network modeling with experimental characterization identifies PRKCA as a novel biomarker and tumor suppressor triggering ferroptosis in prostate cancer.

Yuxin Lin, Zongming Jia, Jixiang Wu, Hubo Yang, Xin Chen, He Wang, Xuedong Wei, Wenying Yan, Xin Qi, Yuhua Huang.

  Prostate cancer (PCa) is observed with high incidence in men worldwide. Ferroptosis, occurred from disorders in a series of gene and pathway regulation, is an emerging target against cancer. However, most of the computational approaches solely treated ferroptosis-related genes (FRGs) as independent variables in model training, and the interactions among FRGs and other candidates were not fully deciphered in a disease-specific content. In this study, a novel network-based and knowledge-guided bioinformatics model was proposed by integrating ferroptosis-related prior knowledge with topological and functional characterization on a protein-protein interaction network for biomarker discovery in PCa development and ferroptosis. The model started at a random walk with restart algorithm for weighting genes close to known FRGs in the PCa-specific network to extract a core subnetwork for robustness and vulnerability analysis. Then key regulatory modules and a candidate gene, i.e. PRKCA, were respectively identified using a multi-level prioritization strategy with hub-bottleneck node filtering, edge-based gene co-expression measuring, community module detecting and a newly defined Ferr.neighbor functional score. The experimental validation using human clinical samples, cell lines, and nude mice convinced the role of PRKCA as a latent biomarker and a tumor suppressor in PCa carcinogenesis with a potential mechanism on triggering GPX4-mediated ferroptosis of PCa cells. This study provides a general-purpose systems biology framework for significant FRG screening, and future translational perspectives of PRKCA as a novel diagnostic and therapeutic signature for PCa management should be explored.

Keywords:  PRKCA; ferroptosis; knowledge-guided modeling; medical systems biology; prostate cancer

DOI:  https://doi.org/10.1093/bib/bbaf220
Methods Enzymol. 2025 ;pii: S0076-6879(25)00112-0. [Epub ahead of print]715 231-239

Targeting polyamine metabolism in an ex vivo prostatectomy model.

Hayley C Affronti, Aryn M Rowsam, Spencer R Rosario, Dominic J Smiraglia.

  Ex vivo models allow for testing drug efficacy and patient response, yet it remains a challenge to develop representative 3D cultures for prostate cancer. Tissue explant models offer a more clinically relevant alternative to organoids due to their ability to provide adequate tissue quantities, maintain tumor-stromal interactions and metabolic activity, and their relatively inexpensive culturing conditions. In this chapter we outline a protocol for culturing patient prostatectomy tumors for up to 7 days on dental sponges soaked in either control or drug containing media for evaluating drug efficacy. Further, we describe the preparation of tissue samples for downstream immunohistochemistry and metabolic analysis. We have tested the efficacy of a combination therapy targeting polyamine metabolism, which is dysregulated in prostate cancer, using this patient tumor explant model. We found that activating polyamine catabolism in combination with inhibition of methionine salvage was effective at inducing target protein expression, reducing intratumoral polyamines, and inducing apoptosis in a majority of the patient samples tested. Additionally, we were able to confirm drug induced effects were specific to the malignant prostate epithelial cells. This ex vivo prostatectomy model lends itself to both targeted metabolite analyses as well as more comprehensive metabolomic analyses. This method can be applied to strategies aiming to target metabolic pathways in solid tumor diseases.

Keywords:  Ex vivo prostatectomy; Metabolomics; Polyamine; Polyamine catabolism; Prostate cancer

DOI:  https://doi.org/10.1016/bs.mie.2025.01.070