bims-meproc Biomed News
on Metabolism in Prostate Cancer
Issue of 2025–07–27
ten papers selected by
Grigor Varuzhanyan, UCLA
  1. The Transcription Axes ERK-Elk1, JNK-cJun, and JAK-STAT Promote Autophagy Activation and Proteasome Inhibitor Resistance in Prostate Cancer Cells.
  2. Dihydrochelerythrine Induced Ferroptosis via Glutathione Peroxidase 4 Downregulation in Prostate Cancer Cells.
  3. Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.
  4. Effects of Docosahexaenoic Acid on Prostate Cancer.
  5. Association of visceral obesity indicators with prostate cancer: a cross-sectional study from Xinjiang.
  6. Dietary antioxidants and flavonoids are inversely associated with prostate cancer risk and mortality: evidence from NHANES and machine learning.
  7. The Effectiveness Of Lipids Derived From Pseudomonas Putida Bacteria In The Formulation Of Nanoliposomes Enhances The Delivery Of Vincristine For The Treatment Of Prostate Cancer.
  8. High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent Applications.
  9. Use of a BMI-independent biomarker-based prostate cancer risk score to identify and triage individuals at risk of prostate disease.
  10. Ectopic Parathyroid Hormone Expression in Nonmetastatic Prostate Cancer.
  1. Curr Issues Mol Biol. 2025 May 12. pii: 352. [Epub ahead of print]47(5):
    The Transcription Axes ERK-Elk1, JNK-cJun, and JAK-STAT Promote Autophagy Activation and Proteasome Inhibitor Resistance in Prostate Cancer Cells.
    Georgios Kalampounias, Kalliopi Zafeiropoulou, Theodosia Androutsopoulou, Spyridon Alexis, Argiris Symeonidis, Panagiotis Katsoris.
      The rapid emergence of resistance limits the application of proteasome inhibitors against solid tumors, despite their effectiveness in the treatment of hematological malignancies. Resistant phenotypes are complex and multifaceted, and, thus, the mechanisms involved have not been adequately described. In this study, a Bortezomib-resistant prostate cancer cell line is created by using the PC-3 cell as a prostate carcinoma model of high metastatic potential. The main biochemical differences and adaptations exhibited by the resistant cells revolve around apoptosis evasion, autophagy induction (functioning as a ubiquitin-proteasome system substitute), expression of epithelial-to-mesenchymal transition markers, and increased aggressiveness. Broad-spectrum signaling pathway analyses also reveal an upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells. Additionally, intracellular reactive oxygen species assays reveal a downregulation in resistant cells, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. These findings expand our understanding of proteasome inhibitor resistance and highlight key kinases and transcription factors as novel potential therapeutic targets. Effective inhibition of resistance-specific pathways could re-sensitize the cells to proteasome inhibitors, thus surpassing current therapeutic limitations.
    Keywords:  Elk1; STAT; autophagy; bortezomib resistance; cJun; oxidative stress; prostate cancer; proteasome-ubiquitin system
    DOI:  https://doi.org/10.3390/cimb47050352
  2. Chem Biodivers. 2025 Jul 20. e00968
    Dihydrochelerythrine Induced Ferroptosis via Glutathione Peroxidase 4 Downregulation in Prostate Cancer Cells.
    Aihua Xu, Yang Xie, Ruobing Han, Jiateng Zhong, Qianqing Wang, Qun Zhou.
      The purpose of this study was to elucidate the role of dihydrochelerythrine (DHC) in prostate cancer and to explore its targets in DU145 and PC3 cells. DHC significantly inhibited the growth of both cell lines. RNA-sequencing analysis revealed that ferroptosis-related genes, including glutathione peroxidase 4 (GPX4) and light chain 3, were significantly downregulated in DHC-treated DU145 cells. Molecular docking studies demonstrated significant interactions between DHC and the GPX4 protein, with a binding energy of -9.01 kcal/mol. Furthermore, GPX4 mRNA expression was significantly upregulated in 497 prostate tumor samples compared to normal tissue in the Cancer Genome Atlas prostate adenocarcinoma dataset. DHC markedly induced ferroptosis in DU145 and PC3 cells by suppressing GPX4 expression, increasing mitochondrial membrane density, and reducing/vanishing mitochondrial cristae, leading to lipid reactive oxygen species production. Treatment with Ferrostatin-1 partially rescued the cell viability reduced by DHC. Collectively, these findings suggest that DHC may be a potential agent for inducing ferroptosis in prostate cancer cells by decreasing GPX4 expression.
    Keywords:  dihydrochelerythrine | ferroptosis | GPX4 | prostate cancer
    DOI:  https://doi.org/10.1002/cbdv.202500968
  3. Cell Commun Signal. 2025 Jul 24. 23(1): 351
    Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.
    Uğur Kahya, Vasyl Lukiyanchuk, Ielizaveta Gorodetska, Matthias M Weigel, Ayşe Sedef Köseer, Berke Alkan, Dragana Savic, Annett Linge, Steffen Löck, Mirko Peitzsch, Ira-Ida Skvortsova, Mechthild Krause, Anna Dubrovska.
       BACKGROUND: Metabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.
    METHODS: The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. γH2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.
    RESULTS: A siRNA-mediated knockdown of Gln transporters SLC1A5, SLC7A5, and SLC38A1 resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters SLC1A5, SLC7A5, or SLC38A1 induces expression of NUPR1, a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from NUPR1 knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.
    CONCLUSIONS: Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.
    Keywords:  GLS; Glutamine transporters; Mitochondria; NUPR1; Oxidative stress; Prostate cancer; Radiation
    DOI:  https://doi.org/10.1186/s12964-025-02344-3
  4. J Xenobiot. 2025 Jul 04. pii: 111. [Epub ahead of print]15(4):
    Effects of Docosahexaenoic Acid on Prostate Cancer.
    Guilherme Henrique Tamarindo, Gustavo Matheus Amaro, Alana Della Torre da Silva, Rejane Maira Góes.
      The polyunsaturated fatty acids of the omega-3 class have been widely investigated due to their antitumor properties, including in prostate cancer (PCa). Among them is docosahexaenoic acid (DHA, C22:6 ω-3), whose biological activity is higher than other omega-3s, exhibiting a stronger impact on PCa. The specific mechanisms triggered by DHA are blurred by studies that used a blend of omega-3s, delaying the understanding of its biological role, and hence alternative therapeutic approaches. DHA is differentially processed between normal and malignant epithelial PCa cells, which suggests its function as a tumor suppressor. At cell-specific level, it downregulates key pathways in PCa, such as androgen signaling and lipid metabolism, but also changes membrane composition by disrupting phospholipid balance and increasing unsaturation status, arrests the cell cycle, and induces apoptosis and reactive oxygen species (ROS) overproduction. At the tissue level, DHA seems to influence stromal components, such as the inhibition of cancer-associated fibroblast differentiation and resolution of inflammation, which generates a microenvironment favorable to PCa initiation and progression. Considering that such effects are misunderstood and assigned to omega-3s in general, this review aims to discuss the specific effects of DHA on PCa based on in vitro and in vivo evidence.
    Keywords:  DHA; PUFAs; fish oil; lipids; omega-3; prostate cancer
    DOI:  https://doi.org/10.3390/jox15040111
  5. Front Oncol. 2025 ;15 1614743
    Association of visceral obesity indicators with prostate cancer: a cross-sectional study from Xinjiang.
    Zhiruo Cai, Xue Guan, Yunyun Xiao, Hengqing An, Ning Tao.
       Background: Prostate cancer (PCa) is a common malignancy among men worldwide, and its risk is strongly associated with obesity, especially visceral obesity. Visceral obesity has been assessed by the visceral adiposity index (VAI), cardiometabolic index (CMI), and lipid accumulation product (LAP), but their associations with PCa remain underexplored. This study investigated the relationship between these visceral obesity indicators and PCa risk.
    Methods: Data for this cross-sectional study were obtained from the First Affiliated Hospital of Xinjiang Medical University from 2022-2023, and 730 participants were screened for the study. A total of 102 PCa patients were included as the PCa group and 102 healthy individuals as the control group using propensity score matching (PSM). We collected anthropometric data (height, weight, waist circumference) and blood biochemical parameters from participants to calculate the VAI, CMI and LAP. These indicators' association and predictive efficacy with PCa were assessed by logistic regression, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curve analysis. The robustness of these results was further examined through sensitivity analyses.
    Results: VAI, CMI, and LAP were higher in the PCa group than in the control group (P<0.05). Logistic regression models showed that VAI, CMI, and LAP were positively associated with PCa. This association of VAI and CMI shows robustness in sensitivity analysis. Compared with the first quartile (Q1), the fourth quartile's (Q4) VAI, CMI and LAP were linked to an increased risk of PCa (OR: 9.07, 95% CI: 3.21-25.65; OR: 11.10, 95% CI: 3.87-31.83; OR: 3.01, 95% CI: 1.17-7.76, respectively). RCS analysis showed that VAI and CMI were nonlinearly associated with PCa risk, and LAP was linearly associated with PCa risk. The area under the ROC curve (AUC) of VAI, CMI, and LAP was 0.721 (95% CI: 0.651-0.791), 0.711 (95% CI: 0.639-0.782), and 0.593 (95% CI: 0.515-0.671), respectively.
    Conclusions: Visceral obesity indicators are closely associated with PCa, of which VAI and CMI show good predictive value and robustness, and can be used as potential biomarkers for assessing PCa risk.
    Keywords:  cardiometabolic index; lipid accumulation product; prostate cancer; visceral adiposity index; visceral obesity indicators
    DOI:  https://doi.org/10.3389/fonc.2025.1614743
  6. Front Nutr. 2025 ;12 1611848
    Dietary antioxidants and flavonoids are inversely associated with prostate cancer risk and mortality: evidence from NHANES and machine learning.
    Yanyang Jin, Dong-Shan Lv, Li-Po Zhou, Li Xiao, Guang-Quan Tong, Abdallah Karim, Shuai Xue, Hongyang Tian, Cheng-Cai Wang, Kun Feng, Ding-Ming Song, You-Liang Guan.
       Background: Oxidative stress and dietary micronutrient imbalances have been implicated in prostate cancer (PCa) development and progression. Although flavonoids and antioxidants show promise in experimental models, evidence from population-based studies remains limited.
    Objectives: This research aimed to investigate the relationship between the consumption of antioxidants and flavonoids in the diet and the risk and survival of PCa, as well as to assess the potential of machine learning models in identifying significant dietary factors.
    Methods: Data from 2,629 male participants aged ≥40 years from National Health and Nutrition Examination Survey (NHANES) 2007-2010 were analyzed. Dietary intake was estimated using two 24-h recalls linked to the USDA Flavonoid Database. PCa status was self-reported. Survey-weighted logistic regression and Cox models evaluated associations with PCa prevalence and all-cause mortality, adjusting for demographic, lifestyle, and clinical covariates. Nine supervised machine learning models, including random forest (RF), were developed and validated. Shapley Additive Explanations (SHAP) values identified key predictors and visualized their effects.
    Results: Among 2,629 U.S. male participants from NHANES 2007-2010, 144 reported a history of PCa. Compared with non-cancer individuals, cases had lower intake of selenium, magnesium, quercetin, kaempferol, epicatechin, epigallocatechin, total flavones, and total flavonoids (all P < 0.05). Higher intake of selenium, magnesium, catechin, and myricetin was associated with reduced PCa risk in weighted regression models, with selenium remaining significant after multivariable adjustment [odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.33-0.76]. Lower intake of selenium, magnesium, luteolin, quercetin, kaempferol, and total flavones was linked to increased mortality risk, and selenium independently predicted improved survival [hazard ratio (HR) = 0.69, 95% CI: 0.54-0.88]. The RF model showed superior predictive performance [area under the curve (AUC) = 0.740], identifying selenium, luteolin, total flavones, myricetin, catechin, and magnesium as key features. SHAP analysis revealed U-shaped associations for selenium, catechin, and myricetin, and dose-dependent protective effects for luteolin and magnesium.
    Conclusion: Our results highlight selenium, magnesium, and select flavonoids as promising dietary factors in reducing PCa risk and improving prognosis. These insights support the development of evidence-based, individualized nutritional strategies and call for further mechanistic and clinical investigations.
    Keywords:  NHANES; antioxidants; flavonoids; machine learning; magnesium; prostate cancer; selenium
    DOI:  https://doi.org/10.3389/fnut.2025.1611848
  7. IEEE Trans Nanobioscience. 2025 Jul 23. PP
    The Effectiveness Of Lipids Derived From Pseudomonas Putida Bacteria In The Formulation Of Nanoliposomes Enhances The Delivery Of Vincristine For The Treatment Of Prostate Cancer.
    Saba Jalilian, Mohammad Javad Hoseinifar, Zahra Asadi, Elham Arkan, Nahid Moarrefzadeh, Faranak Aghaz.
      Prostate cancer (PCa) presents a significant challenge globally due to drug resistance and the severe side effects linked to conventional treatments. In this study, we developed vincristine-loaded nanoliposome-based lipids derived from Pseudomonas putida bacteria (VCR-NLPs) utilizing a thin-layer method. The produced bacteria-lipid-based nanoliposomes represented a critical advancement in drug delivery, offering superior drug encapsulation, controlled release, and enhanced biocompatibility. VCR-NLPs were thoroughly characterized, displaying a spherical morphology with an average particle size of approximately 145 nm, a final zeta potential of -13.1 mV, and a biphasic release profile of VCR. The formulation exhibited efficient drug loading, with 50% release at pH 7.4 and 70% at pH 6, reflecting pH-responsive release behavior tailored to the acidic tumor microenvironment, thereby enhancing therapeutic efficacy. Our flow-cytometric analysis confirmed an efficient induction of late-stage apoptosis in PC3 cells after treatment with VCR-NLPs. These findings suggest that Pseudomonas putida-Lipid-based VCR-NLPs offer a promising nanocarrier system for targeted prostate cancer therapy, due to inducing controlled release of VCR and improving biocompatibility of it, for clinical treatments.
    DOI:  https://doi.org/10.1109/TNB.2025.3591912
  8. J Med Chem. 2025 Jul 25.
    High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent Applications.
    Saheed A Ayodeji, Yaroslav Balytskyi, Destina Unaegbu, Allison Ingman, Christopher V Kelly, Sheryl Roberts.
      Castrate-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) signaling. Imaging tools to monitor AR signaling dynamics are a high-priority goal. Here, we introduce ARi-FL, a series of visible- and near-infrared fluorescent AR inhibitors. Based on an aryloxy cyclohexane scaffold, a neolinker enabled amine-based conjugation to fluorophores. ARi-FL showed potent AR inhibition (IC50 ∼ 13 nM) and allowed visualization of cytoplasmic AR, correlating with AR-expressing cells, which were blockable with excess unlabeled ligand. In vivo and ex vivo studies in human prostate cancer models confirmed ARi-FL localization in AR-positive tumors. In silico modeling across wild-type (WT) and clinically relevant AR mutants (F877L, T878A, H875Y, W742C, and F877L/T878A) revealed nanomolar binding affinities (Kd ∼ 1-2 nM), consistent with experimental results. ARi-FL probes demonstrated high selectivity, practical yields, and stability. Taken together, ARi-FL offers a chemical imaging platform for noninvasive AR tracking with applications for studying resistance mechanisms of AR and guiding treatment decisions.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00836
  9. Sci Rep. 2025 Jul 24. 15(1): 26864
    Use of a BMI-independent biomarker-based prostate cancer risk score to identify and triage individuals at risk of prostate disease.
    Joanne Watt, Allister Irvine, Mary Jo Kurth, Laura Mooney, Gary Smyth, Hardev Pandha, John Lamont, Peter Fitzgerald, Le Roy Dowey, Mark W Ruddock.
      Prostate cancer (PCa) is the second most common cause of cancer related deaths in men in the UK. A national screening programme for PCa does not exist due to the unsuitability of the total prostate specific antigen (tPSA) test which is not specific for PCa and has a high false positive rate. Serum tPSA was measured in n = 25,356 male Randox Health clients. A biomarker-based (tPSA, EGF, MCP-1, IL-8) prostate cancer risk score (PCRS) was then applied to a retrospective cohort (n = 1,142/25,356) of individuals to assess PCa risk. A comparative analysis between tPSA and PCRS indicated that 90.5% of the cohort were assigned low risk of PCa. Of those with an elevated PCRS, 67.8% (78/115) had a normal tPSA value based on tPSA age-adjusted cut-offs. In addition, we observed a significant negative correlation between increasing body mass index (BMI) in men with high BMI (≥ 30) and tPSA levels. No correlation was observed between BMI and PCRS. The tPSA test is potentially unsuitable for use in males with BMI ≥ 30. Use of PCRS could provide more accurate PCa risk stratification for males with BMI ≥ 30. Future assessment of the clinical utility of PCRS is warranted.
    Keywords:  Body mass index; Prostate cancer; Prostate cancer risk score; Prostate specific antigen; Triage
    DOI:  https://doi.org/10.1038/s41598-025-13036-w
  10. JCEM Case Rep. 2025 Sep;3(9): luaf158
    Ectopic Parathyroid Hormone Expression in Nonmetastatic Prostate Cancer.
    Suresh Rama Chandran, Yongcheng Benjamin Tan.
      Ectopic expression of PTH in nonmetastatic prostate cancer is a rare occurrence. We present a case of a 60-year-old Chinese man who initially presented with hyperparathyroidism, PTH 80.1 pg/mL (SI: 8.5 pmol/L) (reference range, 8.5-58.5 pg/mL [SI: 0.9-6.2 pmol/L]), hypophosphatemia, 1.95 mg/dL (SI: 0.63 mmol/L) (reference range, 2.91-4.64 mg/dL [SI: 0.94-1.5 mmol/L]) and normal calcium levels, 2.27 mmol/L (SI 9.08 mg/dL) (reference range, 2.1-2.6 mmol/L [SI: 8.4-10.4 mg/dL]). Two years later, he was diagnosed with prostate adenocarcinoma. A whole-body bone scan ruled out osteoblastic metastases. Notably, the patient exhibited elevated urinary calcium excretion, 304.6 mg/day (SI: 7.6 mmol/day) (reference range, 33.2-272.6 mg/day [SI: 0.82-6.74 mmol/day]) and indeterminate urinary fractional calcium excretion (1.79%). A Technetium-99 sestamibi scan did not identify any hyperfunctioning parathyroid adenoma. Following treatment for prostate cancer, both hyperparathyroidism and hypophosphatemia resolved. Immunostaining of prostate cancer tissue revealed ectopic PTH expression. This case highlights a rare cause of hyperparathyroidism due to ectopic PTH secretion in prostate cancer, adding to known etiologies such as osteoblastic metastases, vitamin D deficiency, oncogenic osteomalacia, renal insufficiency, and primary hyperparathyroidism. Recognizing ectopic PTH expression is crucial for managing prostate cancer patients presenting with hyperparathyroidism.
    Keywords:  ectopic hormone; parathyroid hormone; prostate cancer
    DOI:  https://doi.org/10.1210/jcemcr/luaf158
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