Metabolic adaptations in prostate cancer

British Journal of Cancer, Journal Year: 2024, Volume and Issue: 131(8), P. 1250 - 1262

Published: July 5, 2024

Prostate cancer is one of the most commonly diagnosed cancers in men and a major cause cancer-related deaths worldwide. Among molecular processes that contribute to this disease, weight metabolism has been placed under limelight recent years. Tumours exhibit metabolic adaptations comply with their biosynthetic needs. However, metabolites also play an important role supporting cell survival challenging environments or remodelling tumour microenvironment, thus being recognized as hallmark cancer. uniquely driven by androgen receptor signalling, knowledge influenced paths research. This review provides comprehensive perspective on support prostate progression beyond particular focus intrinsic extrinsic pathways.

Language: Английский

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Enzalutamide Sensitizes Castration‐Resistant Prostate Cancer to Copper‐Mediated Cell Death

Advanced Science, Journal Year: 2024, Volume and Issue: 11(30)

Published: June 10, 2024

Despite the initial efficacy of enzalutamide in castration-resistant prostate cancer (CRPC), inevitable resistance remains a significant challenge. Here, synergistic induction copper-dependent cell death (cuproptosis) CRPC cells is reported by and copper ionophores (elesclomol/disulfiram). Mechanistically, treatment increases mitochondrial dependence cells, rendering them susceptible to cuproptosis, as evidenced specific reversal with chelator tetrathiomolybdate. This susceptibility characterized hallmarks including lipoylated protein aggregation iron-sulfur cluster instability. Interestingly, matrix reductase, FDX1, specifically correlates elesclomol sensitivity, suggesting potential mechanistic divergence between two ionophores. Notably, this effect extends beyond vitro models, demonstrating 22Rv1 xenografts, mouse Pten p53 knockout organoids. Importantly, significantly enhances ionophore-mediated cytotoxicity enzalutamide-resistant cells. Collectively, these findings indicate that synergistically induce offering promising therapeutic avenue for CRPC, potentially cases.

Language: Английский

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MED12 and CDK8/19 modulate androgen receptor activity and enzalutamide response in prostate cancer

Endocrinology, Journal Year: 2024, Volume and Issue: 165(10)

Published: Aug. 27, 2024

Abstract Prostate cancer progression is driven by androgen receptor (AR) activity, which a target for therapeutic approaches. Enzalutamide an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One these expression AR-V7, constitutively active splice variant. The Mediator complex multisubunit protein modulates gene on genome-wide scale. MED12 cyclin-dependent kinase (CDK)8, or paralog CDK19, are components module regulates proliferation cells. In this study, we investigated how CDK8/19 influence cancer-driven processes in cell lines, focusing activity enzalutamide response. We inhibited LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), PC3 (AR−, enzalutamide-insensitive) Both inhibition reduced all respective 3D spheroids. knockdown significantly c-Myc signaling pathways. cells, it consistently response, prostate-specific antigen (PSA) secretion, genes, AR-V7 expression. Combined enzalutamide, additively decreased both PSA secretion cells and, when combined Our study revealed regulate their may modulate response to

Language: Английский

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Mitochondrial Elongation and ROS-Mediated Apoptosis in Prostate Cancer Cells under Therapy with Apalutamide and Complex I Inhibitor

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6939 - 6939

Published: June 25, 2024

Metabolic reprogramming and mitochondrial dynamics are pivotal in prostate cancer (PCa) progression treatment resistance, making them essential targets for therapeutic intervention. In this study, we investigated the effects of androgen receptor antagonist apalutamide (ARN) electron transport chain complex I inhibitor IACS-010759 (IACS) on network architecture PCa cells. Treatment with ARN and/or IACS induced significant changes morphology, particularly elongation, androgen-sensitive Additionally, modulated fission fusion processes, indicating a convergence metabolic androgen-signaling pathways shaping function. Notably, combination resulted increased apoptotic cell death oxidative stress selectively Our findings highlight potential targeting metabolism emphasize need further mechanistic understanding to optimize strategies improve patient outcomes.

Language: Английский

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PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 13, 2024

ABSTRACT Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses thousands patient tumors, we identified enhanced PGC-1α—a potent regulator oxidative phosphorylation (OXPHOS)—in various SCN (SCNCs), closely linked differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing showed elevated PGC-1α expression and increased OXPHOS activity. Inhibition reduced proliferation lung cancer lines blocked tumor formation. Conversely, enhancing PGC- 1α OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled formation rate promoted commitment to ASCL1 lineage. These results establish as driver progression determination, highlighting novel vulnerabilities SCNCs across different tissues. STATEMENT OF SIGNIFICANCE Our study provides functional evidence that reprogramming impact phenotypes establishes PGC-1α-induced lineage determination. mechanistic insights reveal common originating tissues, opening new avenues for pan-SCN therapeutic strategies.

Language: Английский

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A Metabolic–Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer

Cancer Research, Journal Year: 2024, Volume and Issue: 84(9), P. 1382 - 1383

Published: Feb. 8, 2024

Abstract Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that cell's lineage both drives is governed by its specific metabolic features. A recent study Zhang colleagues, published in Cell Metabolism, describes novel metabolic–epigenetic regulatory axis governs identity triple-negative breast cancer (TNBC). Among key findings, authors demonstrate enzyme pyruvate kinase M2 (PKM2) directly binds to histone methyltransferase enhancer of zeste homolog 2 (EZH2) nucleus silence expression set genes includes mitochondrial carnitine transporter SLC16A9. Perturbation this mechanism induces shift away from glycolysis toward fatty acid oxidation. The ensuing influx facilitates deposition activating epigenetic mark H3K27Ac onto promoter GATA3, driving committed luminal state. Importantly, represents potentially targetable vulnerability for treatment TNBC, subtype currently lacks effective therapeutic strategies. These findings lend further support paradigm underlying our understanding metabolism: fuel source functions not only provide energy but also direct regulation fate.

Language: Английский

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UBXN1 promotes liver tumorigenesis by regulating mitochondrial homeostasis

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: May 21, 2024

The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases cell survival growth. molecular events controlling integrity that facilitate the development hepatocellular carcinoma (HCC) remain unclear. Here, we report UBX domain-containing protein 1 (UBXN1) hyperactivation essential liver tumorigenesis.

Language: Английский

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PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(49)

Published: Nov. 26, 2024

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands patient tumors human lines uncovered enhanced expression proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased the lineage marker Achaete-scute homolog 1, (ASCL1) through positive feedback mechanism. Analyses using prostate tissue-based transformation system showed that ASCL1 subtype has heightened OXPHOS activity. inhibition diminished OXPHOS, reduced SCNC proliferation, blocked tumor formation. Conversely, overexpression validated by small-animal Positron Emission Tomography imaging, tripled formation rate, promoted commitment lineage. These results establish as driver progression determination, highlighting metabolic vulnerabilities in SCNCs different tissues.

Language: Английский

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Personalized Medicine: Leave no Patient Behind; Report From the 2024 Coffey‐Holden Prostate Cancer Academy Meeting

The Prostate, Journal Year: 2024, Volume and Issue: 85(3), P. 211 - 226

Published: Nov. 27, 2024

ABSTRACT Introduction The 11th Annual 2024 Coffey ‐ Holden Prostate Cancer Academy (CHPCA) Meeting, was themed “Personalized Medicine: Leave No Patient Behind,” and held from June 20 to 23, at the University of California, Los Angeles, Luskin Conference Center, in CA. Methods CHPCA Meeting is an academy‐styled annual conference organized by Foundation, focus discussion on most critical emerging research that have greatest potential advance knowledge prostate cancer biology treatment. attended 75 academic investigators included 37 talks across 8 sessions. Results meeting sessions focused on: novel human, mouse systems models, immunotherapies for cancer, efforts overcome treatment resistance, role metabolism diet as a therapeutic target, mechanisms drive differentiation into neuroendocrine subtypes, evolving epigenome disease progression machine learning advanced computational approaches precision oncology. Discussion This article summarizes presentations discussions Meeting. We hope sharing this will inspire accelerate new discoveries solutions cancer.

Language: Английский

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