Fatty acid metabolism is essential for the biogenesis of cellular components and ATP production to sustain proliferation of cancer cells. Long-chain fatty acyl-CoA synthetases (ACSLs), a group of rate-limiting enzymes in fatty acid metabolism, catalyze the bioconversion of exogenous or de novo synthesized fatty acids to their corresponding fatty acyl-CoAs. In this study, systematical analysis of ACSLs levels and the amount of fatty acyl-CoAs illustrated that ACSL1 were significantly associated with the levels of a broad spectrum of fatty acyl-CoAs, and were elevated in human prostate tumors. ACSL1 increased the biosynthesis of fatty acyl-CoAs including C16:0-, C18:0-, C18:1-, and C18:2-CoA, triglycerides and lipid accumulation in cancer cells. Mechanistically, ACSL1 modulated mitochondrial respiration, β-oxidation, and ATP production through regulation of CPT1 activity. Knockdown of ACSL1 inhibited the cell cycle, and suppressed the proliferation and migration of prostate cancer cells in vitro, and growth of prostate xenograft tumors in vivo. Our study implicates ACSL1 as playing an important role in prostate tumor progression, and provides a therapeutic strategy of targeting fatty acid metabolism for the treatment of prostate cancer.
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Butler LM, Centenera MM, Swinnen JV. Androgen control of lipid metabolism in prostate cancer: novel insights and future applications. Endocr Relat Cancer. 2016;23:R219–27.
Wu X, Daniels G, Lee P, Monaco ME. Lipid metabolism in prostate cancer. Am J Clin Exp Urol. 2014;2:111–20.
Currie E, Schulze A, Zechner R, Walther TC, Farese RV. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–61.
Yan S, Yang XF, Liu HL, Fu N, Ouyang Y, Qing K. Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. World J Gastroenterol. 2015;21:3492–8.
Kim S, Alsaidan OA, Goodwin O, Li Q, Sulejmani E, Han Z, et al. Blocking myristoylation of Src inhibits its kinase activity and suppresses prostate cancer progression. Cancer Res. 2017;77:6950–62.
Kim S, Yang X, Li Q, Wu M, Costyn L, Beharry Z, et al. Myristoylation of Src kinase mediates Src-induced and high-fat diet-accelerated prostate tumor progression in mice. J Biol Chem. 2017;292:18422–33.
Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med. 2008;233:507–21.
Mashima T, Oh-hara T, Sato S, Mochizuki M, Sugimoto Y, Yamazaki K, et al. p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J Natl Cancer Inst. 2005;97:765–77.
Grevengoed TJ, Klett EL, Coleman RA. Acyl-CoA metabolism and partitioning. Annu Rev Nutr. 2014;34:1–30.
Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV Jr. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res. 2008;49:2283–301.
Wang YY, Attane C, Milhas D, Dirat B, Dauvillier S, Guerard A, et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. Jci Insight. 2017;2:e87489.
Lee K, Kerner J, Hoppel CL. Mitochondrial carnitine palmitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid transfer complex. J Biol Chem. 2011;286:25655–62.
Bieber LL, Abraham T, Helmrath T. A rapid spectrophotometric assay for carnitine palmitoyltransferase. Anal Biochem. 1972;50:509–18.
Vargas T, Moreno-Rubio J, Herranz J, Cejas P, Molina S, Gonzalez-Vallinas M, et al. ColoLipidGene: signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients. Oncotarget. 2015;6:7348–63.
Sanchez-Martinez R, Cruz-Gil S, de Cedron MG, Alvarez-Fernandez M, Vargas T, Molina S, et al. A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy. Oncotarget. 2015;6:38719–36.
Iijima H, Fujino T, Minekura H, Suzuki H, Kang MJ, Yamamoto T. Biochemical studies of two rat acyl-CoA synthetases, ACS1 and ACS2. Eur J Biochem. 1996;242:186–90.
Li LO, Ellis JM, Paich HA, Wang S, Gong N, Altshuller G, et al. Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition. J Biol Chem. 2009;284:27816–26.
Ellis JM, Mentock SM, Depetrillo MA, Koves TR, Sen S, Watkins SM, et al. Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy. Mol Cell Biol. 2011;31:1252–62.
Yang X, Ma Y, Li N, Cai H, Bartlett MG. Development of a method for the determination of Acyl-CoA compounds by liquid chromatography mass spectrometry to probe the metabolism of fatty acids. Anal Chem. 2017;89:813–21.
Wu X, Deng F, Li Y, Daniels G, Du X, Ren Q, et al. ACSL4 promotes prostate cancer growth, invasion and hormonal resistance. Oncotarget. 2015;6:44849–63.
Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab. 2014;19:393–406.
Koizume S, Miyagi Y. Lipid droplets: a key cellular organelle associated with cancer cell survival under normoxia and hypoxia. Int J Mol Sci. 2016;17:1430.
Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L, et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther. 2014;13:2361–71.
Lloyd MD, Yevglevskis M, Lee GL, Wood PJ, Threadgill MD, Woodman TJ. alpha-Methylacyl-CoA racemase (AMACR): metabolic enzyme, drug metabolizer and cancer marker P504S. Prog Lipid Res. 2013;52:220–30.
Grevengoed TJ, Martin SA, Katunga L, Cooper DE, Anderson EJ, Murphy RC, et al. Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function. J Lipid Res. 2015;56:1572–82.
Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc Natl Acad Sci USA. 1994;91:6379–83.
Epstein JI, Carmichael M, Partin AW. Oa-519 (fatty-acid synthase) as an independent predictor of pathological stage in adenocarcinoma of the prostate. Urology. 1995;45:81–6.
Kuemmerle NB, Rysman E, Lombardo PS, Flanagan AJ, Lipe BC, Wells WA, et al. Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther. 2011;10:427–36.
Gazi E, Gardner P, Lockyer NP, Hart CA, Brown MD, Clarke NW. Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy. J Lipid Res. 2007;48:1846–56.
Folch J, Lees M, Sloane, Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226:497–509.
This work was supported by NIH (R01CA172495) and DOD (W81XWH-15-1-0507) to HC.
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Ma, Y., Zha, J., Yang, X. et al. Long-chain fatty acyl-CoA synthetase 1 promotes prostate cancer progression by elevation of lipogenesis and fatty acid beta-oxidation. Oncogene 40, 1806–1820 (2021). https://doi.org/10.1038/s41388-021-01667-y