Conclusion
This study shifts the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs. Targeting DGAT1-mediated LD biogenesis is a promising strategy to restrict lipid mediator production and tumour growth.
Methods
We combined lipidomic and functional analyses in cancer cell line models to dissect the trafficking of PUFAs between membrane phospholipids and LDs and determine the role of these pathways in lipid mediator production, cancer cell proliferation and tumour growth in vivo.
Results
We demonstrate that lipid mediator production strongly depends on TAG turnover. GX sPLA2 directs ω-3 and ω-6 PUFAs from membrane phospholipids into TAG stores, whereas ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL controls the release of PUFAs from LD stores and their conversion into cyclooxygenase- and lipoxygenase-derived lipid mediators under conditions of nutrient sufficiency and during serum starvation. In starving cells, ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids, representing substrates for cPLA2α. Furthermore, we demonstrate that the built-up of TAG stores by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is required for the production of mitogenic lipid signals that promote cancer cell proliferation and tumour growth.