Lipid droplets control mitogenic lipid mediator production in human cancer cells

Abstract

Polyunsaturated fatty acids (PUFAs) are components of membrane phospholipids and precursors of bioactive lipid mediators. Here, we investigated the crosstalk of three pathways providing PUFAs for lipid mediator production: (i) secreted group X phospholipase A2 (GX sPLA2) and (ii) cytosolic group IVA PLA2 (cPLA2), which both mobilize PUFAs from phospholipids, and (iii) adipose triglyceride lipase (ATGL), which breaks down triacylglycerols (TAGs) stored in lipid droplets (LDs). Combining lipidomic and functional analyses, we demonstrate that lipid mediator production depends on TAG turnover. GX sPLA2 directs PUFAs into TAGs and ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids representing substrates for cPLA2. Additionally, inhibition of TAG synthesis mediated by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) reduces the levels of mitogenic lipid signals and compromises tumour growth. This study expands the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs.