Fatty acid elongation regulates mitochondrial β-oxidation and cell viability in prostate cancer by controlling malonyl-CoA levels.

Autor: Scott JS; South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Quek LE; School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, 2006, Australia., Hoy AJ; School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia., Swinnen JV; LKI - Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven, B-3000, Belgium., Nassar ZD; South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Butler LM; South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, 5005, Australia; Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia. Electronic address: lisa.butler@adelaide.edu.au.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Jan 08; Vol. 691, pp. 149273. Date of Electronic Publication: 2023 Nov 18.
DOI: 10.1016/j.bbrc.2023.149273
Abstrakt: Recently, the fatty acid elongation enzyme ELOVL5 was identified as a critical pro-metastatic factor in prostate cancer, required for cell growth and mitochondrial homeostasis. The fatty acid elongation reaction catalyzed by ELOVL5 utilizes malonyl-CoA as the carbon donor. Here, we demonstrate that ELOVL5 knockdown causes malonyl-CoA accumulation. Malonyl-CoA is a cellular substrate that can inhibit fatty acid β-oxidation in the mitochondria through allosteric inhibition of carnitine palmitoyltransferase 1A (CPT1A), the enzyme that controls the rate-limiting step of the long chain fatty acid β-oxidation cycle. We hypothesized that changes in malonyl-CoA abundance following ELOVL5 knockdown could influence mitochondrial β-oxidation rates in prostate cancer cells, and regulate cell viability. Accordingly, we find that ELOVL5 knockdown is associated with decreased mitochondrial β-oxidation in prostate cancer cells. Combining ELOVL5 knockdown with FASN inhibition to increase malonyl-CoA abundance endogenously enhances the effect of ELOVL5 knockdown on prostate cancer cell viability, while preventing malonyl-CoA production rescues the cells from the effect of ELOVL5 knockdown. Our findings indicate an additional role for fatty acid elongation, in the control of malonyl-CoA homeostasis, alongside its established role in the production of long-chain fatty acid species, to explain the importance of fatty acid elongation for cell viability.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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