Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, and Division of Cell and Developmental Biology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):14912-7. doi: 10.1073/pnas.1310894110. Epub 2013 Aug 26.
Aberrant lipid metabolism is an established hallmark of cancer cells. In particular, ether lipid levels have been shown to be elevated in tumors, but their specific function in cancer remains elusive. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a critical step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. We demonstrate that ablation of AGPS in cancer cells results in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acid-derived glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids. Taken together, our results reveal that AGPS, in addition to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer.
异常的脂质代谢是癌细胞的一个既定特征。特别是，醚脂水平已被证明在肿瘤中升高，但它们在癌症中的具体功能仍不清楚。我们在这里表明，代谢酶烷基甘油磷酸合酶（AGPS），是醚脂合成的关键步骤，在多种侵袭性人类癌细胞和原发性肿瘤中都被上调。我们证明，在癌细胞中敲除 AGPS 会通过改变醚脂、脂肪酸、类二十烷酸和脂肪酸衍生的甘油磷脂代谢的平衡，从而降低细胞存活率、癌症侵袭性和肿瘤生长，导致几种致癌信号脂质的水平总体降低。总之，我们的结果表明，AGPS 除了维持醚脂外，还控制着细胞对脂肪酸的利用，有利于产生促进癌症侵袭性特征所必需的信号脂质。
