Belkaid Anissa, Ouellette Rodney J, Surette Marc E
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada and.
Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada.
Carcinogenesis. 2017 Apr 1;38(4):402-410. doi: 10.1093/carcin/bgx020.
Long chain acyl-CoA synthase-4 (ACSL4) expression has been associated with an aggressive phenotype in breast carcinoma cells, whereas its role in ERα-positive breast cancer has not been studied. ACSL4 prefers 20-carbon polyunsaturated fatty acid (PUFA) substrates, and along with other ACSLs has been associated with cellular uptake of exogenous fatty acids. 17β-estradiol induces proliferation and invasive capacities in ERα+ve breast carcinoma that is associated with modifications of cellular lipid metabolism. In this study, treatment of steroid-starved ERα-positive MCF-7 and T47D mammary carcinoma cells with 17β-estradiol resulted in increased cellular uptake of the PUFA arachidonic acid (AA) and eicosapentaenoic acid (EPA), important building blocks for cellular membranes, and increased ACSL4 protein levels. There was no change in the expression of the ACSL1, ACSL3 and ACSL6 protein isotypes. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life compared to untreated cells. ERα silencing reversed the impact of 17β-estradiol on ACSL4 protein levels and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in AA and EPA uptake, as well as the 17β-estradiol-induced cell migration, proliferation and invasion capacities. ASCL4 silencing also prevented the 17β-estradiol induced increases in p-Akt and p-GSK3β, and decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. Taken together, these results demonstrate that ACSL4 is a target of 17β-estradiol-stimulated ERα and is required for the cellular uptake of exogenous PUFA and the manifestation of a more malignant phenotype in ERα+ve breast carcinoma cells.
长链脂酰辅酶A合成酶4（ACSL4）的表达与乳腺癌细胞的侵袭性表型相关，而其在雌激素受体α（ERα）阳性乳腺癌中的作用尚未得到研究。ACSL4更倾向于以20碳多不饱和脂肪酸（PUFA）为底物，并且与其他ACSLs一起参与了细胞对外源脂肪酸的摄取。17β-雌二醇可诱导ERα阳性乳腺癌细胞的增殖和侵袭能力，这与细胞脂质代谢的改变有关。在本研究中，用17β-雌二醇处理缺乏类固醇的ERα阳性MCF-7和T47D乳腺癌细胞，导致细胞膜重要组成部分PUFA花生四烯酸（AA）和二十碳五烯酸（EPA）的细胞摄取增加，以及ACSL4蛋白水平升高。ACSL1、ACSL3和ACSL6蛋白亚型的表达没有变化。ACSL4蛋白表达的增加并未伴随ACSL4 mRNA表达的改变，但与未处理细胞相比，其蛋白半衰期显著延长。ERα沉默逆转了17β-雌二醇对ACSL4蛋白水平和半衰期的影响。ACSL4沉默消除了17β-雌二醇诱导的AA和EPA摄取增加，以及17β-雌二醇诱导的细胞迁移、增殖和侵袭能力。ASCL4沉默还阻止了17β-雌二醇诱导的p-Akt和p-GSK3β增加以及E-钙黏蛋白表达降低，这些是上皮-间质转化中的重要事件。综上所述，这些结果表明ACSL4是17β-雌二醇刺激的ERα的靶点，是ERα阳性乳腺癌细胞摄取外源PUFA和表现出更恶性表型所必需的。
