title: Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines.
abstract: 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. β-catenin, caspase-3/8, Bcl-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.
authors.affiliation: Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration, Tianjin, China E-mail : zhuyutj@126.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xing-Jun
authors.initials: XJ
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Lv
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005910:Glioma / Q000188:drug therapy*; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D008246:Lysophospholipids / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019883:Alkyl and Aryl Transferases; D053148:Caspase 3; D053181:Caspase 8; D015232:Dinoprostone; D051034:Inhibitor of Apoptosis Proteins; D008246:Lysophospholipids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D000077022:Survivin; D051176:beta Catenin; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C107489:BIRC5 protein, human; C019654:alkylglycerone-phosphate synthase; C032881:lysophosphatidic acid; C421109:multidrug resistance-associated protein 1