Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines

  • Zhu, Yu (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration) ;
  • Liu, Xing-Jun (Department of Neurosurgery, Tianjin Haihe Hospital) ;
  • Yang, Ping (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration) ;
  • Zhao, Meng (Department of Immunology and Department of Biochemistry, School of Basic Medical Sciences, Tianjin Medical University) ;
  • Lv, Li-Xia (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration) ;
  • Zhang, Guo-Dong (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration) ;
  • Wang, Qin (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration) ;
  • Zhang, Ling (Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration)
  • 발행 : 2014.04.01


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, 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.


  1. Tani K, Naganawa A, Ishida A, et al (2001). Design and synthesis of a highly selective EP2-receptor agonist. Bioorg Med Chem Lett, 11, 2025-8.
  2. Vander Heiden MG, Cantley LC, Thompson CB (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324, 1029-33.
  3. Weinstein D, Sarfstein R, Laron Z, et al (2014). Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells. Endocr Connect, 3, 24-35.
  4. Woodward DF, Protzman CE, Krauss AH, et al (1993). Identification of 19 (R)-OH prostaglandin E2 as a selective prostanoid EP2-receptor agonist. Prostaglandins, 46, 371-83.
  5. Mita AC, Mita MM, Nawrocki ST, et al (2008). Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res, 14, 5000-5.
  6. Louisa M, Soediro TM, Suyatna FD (2014). In vitro modulation of P-glycoprotein, MRP-1 and BCRP Expression by Mangiferin in Doxorubicin-Treated MCF-7 Cells. Asian Pac J Cancer Prev, 15, 1639-42.
  7. Madan D, Ferguson CG, Lee WY, et al (2013). Non-invasive imaging of tumors by monitoring autotaxin activity using an enzyme-activated near-infrared fluorogenic substrate. PLoS One, 8, 79065.
  8. Marquardt JU, Andersen JB (2012). Next-generation sequencing: application in liver cancer-past, present and future? Biology, 1, 383-94.
  9. Morandi A, Chiarugi P (2014). Metabolic implication of tumor:stroma crosstalk in breast cancer. J Mol Med, 92, 117-26.
  10. Nomura DK, Long JZ, Niessen S, et al (2010). Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell, 140, 49-61.
  11. Pommier Y, Leo E, Zhang H, et al (2010). DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol, 17, 421-33.
  12. Prabhu AV, Krycer JR, Brown AJ (2013). Overexpression of a key regulator of lipid homeostasis, Scap, promotes respiration in prostate cancer cells. FEBS Lett, 587, 983-8.
  13. Srivastava AN, Gupta A, Srivastava S, et al (2010). Cisplatin combination chemotherapy induces oxidative stress in advance non small cell lung cancer patients. Asian Pac J Cancer Prev, 11, 465-71.
  14. Takaoka K, Kishimoto H, Segawa E, et al (2008). In vitro susceptibility to anticancer agents of the human KB carcinoma cell line transfected with COX-2 cDNA. Oncol Rep, 20, 645-9.
  15. Hull MA, Ko SC, Hawcroft G (2004). Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther, 3, 1031-9.
  16. Han C, Michalopoulos GK, Wu T (2006). Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J Cell Physiol, 207, 261-70.
  17. Henderson MJ, Haber M, Porro A, et al (2011). ABCC multidrug transporters in childhood neuroblastoma: clinical and biological effects independent of cytotoxic drug efflux. J Natl Cancer Inst, 103, 1236-51.
  18. Hu S, Sun W, Wei W, et al (2013). Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis. Anticancer Drugs, 24, 140-9.
  19. Kambe A, Iguchi G, Moon Y, et al (2008). Regulation of EP4 expression via the Sp-1 transcription factor: inhibition of expression by anti-cancer agents. Biochim Biophys Acta, 1783, 1211-9.
  20. Kashiwagi E, Shiota M, Yokomizo A, et al (2013). Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells. Endocr Relat Cancer, 20, 431-41.
  21. Krysan K, Merchant FH, Zhu L, et al (2004). COX-2-dependent stabilization of survivin in non-small cell lung cancer. FASEB J, 18, 206-8.
  22. Liu F1, Wei WQ, Cormier RT, et al (2014). Association of single nucleotide polymorphisms in the prostaglandinendoperoxide synthase 2 (PTGS2) and phospholipase A2 Group IIA (PLA2G2A) genes with susceptibility to esophageal squamous cell carcinoma. Asian Pac J Cancer Prev, 15, 1797-802.
  23. Aust S, Pils S, Polterauer S, et al (2013). Expression of Bcl-2 and the antiapoptotic BAG family proteins in ovarian cancer. Appl Immunohistochem Mol Morphol, 21, 518-24.
  24. Benjamin DI, Cozzo A, Ji X, et al (2013). Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity. Proc Natl Acad Sci USA, 110, 14912-7.
  25. Blackburn J, Mansell JP (2012). The emerging role of lysophosphatidic acid (LPA) in skeletal biology. Bone, 50, 756-62.
  26. Brindley DN, Lin FT, Tigyi GJ (2013). Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy. Biochim Biophys Acta, 1831, 74-85.
  27. Castellone MD, Teramoto H, Williams BO, et al (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science, 310, 1504-10.
  28. Gillibert-Duplantier J, Neaud V, Blanc JF, et al (2007). Thrombin inhibits migration of human hepatic myofibroblasts. Am J Physiol Gastrointest Liver Physiol, 293, 128-36.
  29. Greenhough A, Smartt HJ, Moore AE, et al (2009). The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis, 30, 377-86.

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