The innate immune mediator group IIA secreted phospholipase A2 modulates lipid droplet formation in prostate cancer cells

Introduction: (hGIIA) has both catalysis-dependent and -independent functions that are associated with both acute and chronic inflammatory disorders including cancer. Our novel inhibitors that selectively block hGIIA's catalysis-independent function slow tumor growth in animal models via interaction with vimentin. The mechanism of this interaction and its consequences for cancer aggressiveness remains unexplored. Methods: ) cells treated with hGIIA protein in the presence and absence of our cyclic peptide inhibitor Kesonotide (also known as c2). As lipid metabolism is known to be regulated by vimentin, we examined whether this aspect of vimentin biology was influenced by interaction with hGIIA, focusing on lipid droplet (LD) formation, LD-associated perilipin proteins (PLIN2 and PLIN3) and lipid biosynthetic enzymes (DGAT and FASN). To do this we used the combination of single cell quantitative immunofluorescence and Western blot analysis. Results: We found that addition of exogenous hGIIA increased LD metabolism as evidenced by LD immunofluorescence signal and this increase is dependent on vimentin in PCa. The response is dependent on hGIIA levels with high concentrations of hGIIA associated with PLIN2 loss, PLIN3 suppression, and DGAT1 induction without FASN upregulation. Kesonotide alone was largely inert. However, at high concentration of hGIIA, Kesonotide attenuated lipid metabolism by neutralizing perilipin remodelling and attenuating DGAT1 induction in knockout cells. Discussion: Taken together, these findings identify a context-dependent hGIIA LD-remodelling program that is shaped by vimentin, implicating for the first time the hGIIA-vimentin axis in inflammatory cue-driven lipid metabolic rewiring in aggressive PCa.