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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / biosynthesis
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / biosynthesis
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Alkyl and Aryl Transferases / genetics*
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Apoptosis / genetics
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Carcinoma, Hepatocellular / drug therapy*
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Caspase 3 / biosynthesis
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Caspase 8 / biosynthesis
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cell Proliferation / genetics
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Dinoprostone / metabolism
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Drug Resistance, Neoplasm / genetics*
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Glioma / drug therapy*
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Hep G2 Cells
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Humans
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Inhibitor of Apoptosis Proteins / biosynthesis
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Lipid Metabolism
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Liver Neoplasms / drug therapy*
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Lysophospholipids / metabolism
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Multidrug Resistance-Associated Proteins / biosynthesis
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Neoplasm Proteins / biosynthesis
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA Interference
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RNA, Small Interfering
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Receptors, Lysophosphatidic Acid / metabolism
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Signal Transduction
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Survivin
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beta Catenin / biosynthesis
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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Lysophospholipids
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Receptors, Lysophosphatidic Acid
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Survivin
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beta Catenin
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Alkyl and Aryl Transferases
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alkylglycerone-phosphate synthase
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Caspase 3
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Caspase 8
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Dinoprostone
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lysophosphatidic acid
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multidrug resistance-associated protein 1