Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines
Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines
复制标题
DOI：
10.7314/apjcp.2014.15.7.3219
复制
发表时间：
2014-01-01
影响因子：
--
通讯作者：
Zhang, Ling
中科院分区：
文献类型：
--
作者：
Zhu, Yu;Liu, Xing-Jun;Zhang, Ling
化疗仍然是癌症治疗的主要手段，尽管耐药性是一个主要障碍。脂质代谢在癌症病理学中起关键作用，具有升高的醚脂质水平。最近，烷基甘油磷酸合酶（AGPS），一种催化醚脂质合成的关键步骤的酶，被证明在多种类型的癌细胞和原发性肿瘤中上调。在此，我们证明了在化疗抗性胶质瘤U87 MG/DDP和肝癌HepG 2/ADM细胞系中沉默AGPS通过降低细胞内溶血磷脂酸（LPA）、溶血磷脂酸-醚（LPAe）和前列腺素E2（PGE 2）的浓度而导致细胞增殖降低、药物敏感性增加、细胞周期阻滞和细胞凋亡，导致LPA受体和EP受体介导的PI 3 K/AKT信号通路的减少以及几种多药耐药基因如MDR 1、MRP 1和ABCG 2的表达。β-catenin、caspase-3/8、Bc 1 -2和survivin也参与了细胞凋亡。总之，我们的研究表明，AGPS通过介导癌细胞中的信号脂质代谢在癌症化疗抗性中起作用。
Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. beta-catenin, caspase-3/8, Bc1-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.