Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity
Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity
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DOI：
10.1073/pnas.1310894110
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发表时间：
2013-09-10
影响因子：
11.1
通讯作者：
Nomura, Daniel K.
中科院分区：
文献类型：
--
作者：
Benjamin, Daniel I.;Cozzo, Alyssa;Nomura, Daniel K.
脂质代谢异常是癌细胞的一个既定标志。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然难以捉摸。我们在此表明，代谢酶烷基甘油磷酸合酶（AGPS）是合成醚脂质的关键步骤，在多种类型的侵袭性人类癌细胞和原发性肿瘤中上调。我们证明，癌细胞中 AGPS 的消融通过改变醚脂、脂肪酸、类二十烷酸和脂肪酸衍生的甘油磷脂代谢的平衡，导致细胞存活率、癌症侵袭性和肿瘤生长降低，从而导致几种致癌信号脂质水平的总体降低。总而言之，我们的结果表明，AGPS 除了维持醚脂质外，还控制细胞对脂肪酸的利用，有利于促进癌症侵袭性特征所需的信号脂质的产生。
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.