Lipid droplets (LD) enable cancer cells to adapt to stressful conditions in their microenvironment. LD biogenesis is driven by triglyceride synthesis mediated by diacylglycerol acyltransferases (DGAT) 1 and 2. Our recent studies have shown that apart from their role in energy and redox homeostasis, LDs are also important for the production of pro-tumorigenic lipid mediators, also mediating phospholipase A2 (PLA2)-induced lipid mediator production. We asked whether the inhibition of DGAT1 and DGAT2 enzymes affects cancer cell proliferation and migration and whether the effect of human group X secreted phospholipase A2 (hGX sPLA2) on cancer cell proliferation depends on LDs. We show that LD biogenesis in A549 lung cancer and MDA-Luc-RFP breast cancer cells was supressed by combined inhibition of DGAT1 and DGAT2 enzymes, leading to reduced cancer cell proliferation and migration. Treatments with hGX sPLA2 induced LD formation and increased the rate of proliferation in both cell lines, but its effects were reversed by the combination of both DGAT inhibitors. We also found that knockdown of the intracellular group IVA cytosolic PLA2 (cPLA2α), the canonical enzyme driving eicosanoid production, decreased the proliferation of A549 cells and suppressed the proliferative effect of the sPLA2. This work demonstrates that triglyceride biosynthesis and LD biogenesis drive cancer cell proliferation and also mediate the mitogenic effects of group X and group IVA PLA2s.
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