Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Abstract

Aberrant lipid metabolism is an established hallmark of cancer cells. In particular, ether lipid levels have been shown to be elevated in tumors, but their specific function in cancer remains elusive. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a critical step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. We demonstrate that ablation of AGPS in cancer cells results in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acidderived glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids. Taken together, our results reveal that AGPS, in addition to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer.cancer metabolism | metabolomics | lipid signaling lysophosphatidic acid | eicosanoids

Interaction of Phospholipase A/Acyltransferase-3 with Pex19p

“…Based on our present results, PLA/AT-3 may affect the oncogenic activity and/or intracellular localization of H-Ras by altering the membrane structure through the reduction in the content of ether-type lipids. It was also reported that aggressive cancer cells possess significantly higher levels of ether-type lipids than less aggressive counterparts (53). Aggressive cancer cells highly expressed ADHAPS, an enzyme involved in the biosynthesis of the ether-type lipids, and the transformation of less aggressive cancer cells with H-Ras up-regulated ADHAPS expression, leading to an increase in the levels of ether-type lipids.…”

Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis

“…Altered metabolic pathways in cancer cells may be attractive targets for anticancer therapy. For example, inhibition of alkylglycerone phosphate synthase (AGPS), a critical enzyme for ether lipid synthesis, results in impairments in cancer pathogenicity by reduction of ether lipids and alterations of fatty acid, eicosanoid, and glycerophospholipid metabolism [56]. Knockdown of CKB inhibits cell proliferation and induces apoptosis in ovarian cancer Skov3 cell line by decreasing glycolysis [57].…”

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

“…Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipids synthesis, is shown to up-regulate in multiple types of cancer cell and primary tumor. AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity (Benjamin et al, 2013). Nonetheless, whether AGPS is involved in chemotherapy resistance has remained unclear.…”