Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines.

Guo-Dong Zhang,Xing-Jun Liu,Li-Xia Lv,Meng Zhao,Qin Wang,Yu Zhu,Ling Zhang,Ping Yang

doi:10.7314/apjcp.2014.15.7.3219

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.

Highlights

The hallmarks of cancer are keys for cancer treatment
We demonstrated that silencing of alkylglyceronephosphate synthase (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. ơFDWHQLQFDVSDVH%FODQGVXUYLYLQZHUHDOVRIRXQGWREHLQYROYHG,QVXPPDU\RXUVWXGLHVLQGLFDWHWKDW AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells
In order to investigate the role of AGPS in chemotherapy resistance, we used lentivirus to knockdown AGPS in several drug-resistant cancer cell lines in this study

Summary

Introduction

The most fundamental hallmark of cancer cells is their ability to sustain proliferation (Marquardt et al, 2012). This trait is the target of chemotherapy agents, an old but still widely used class of cancer therapeutic medicine. One type is called alkylating agents, the typical drug is cisplatin (Srivastava et al, 2010). Another type is topoisomerase inhibitors, with doxorubicin is the typical one (Pommier et al, 2010). Cisplatin and doxorubicin are extensively used to treatment different types of cancer. Resistance to these drugs is rather common

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Conclusion