ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis.

Autor:	Shrestha RK; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Australia.; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, Australia., Nassar ZD; South Australian Health and Medical Research Institute, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, Australia., Hanson AR; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, Australia., Iggo R; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Institut Bergonié Unicancer, INSERM, Bordeaux, France., Townley SL; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, Australia., Dehairs J; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium., Mah CY; South Australian Health and Medical Research Institute, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, Australia., Helm M; South Australian Health and Medical Research Institute, Adelaide, Australia., Alizadeh-Ghodsi M; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, Australia., Pickering M; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia., Ghesquière B; Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB, Leuven, Belgium.; Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium., Watt MJ; Department of Physiology, University of Melbourne, Melbourne, Australia., Quek LE; School of Mathematics and Statistics, Charles Perkins Centre, Faculty of Science, The University of Sydney, Camperdown, Australia., Hoy AJ; School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia., Tilley WD; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, Australia., Swinnen JV; Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium., Butler LM; South Australian Health and Medical Research Institute, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, Australia., Selth LA; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Australia.; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, Australia.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Jul 15; Vol. 84 (14), pp. 2313-2332.
DOI:	10.1158/0008-5472.CAN-23-1489
Abstrakt:	Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu