Inflammation, mediated in part by the innate immune response, is a key driver of tumour growth and metastasis in cancer. The molecular factors that mediate the pro-tumourigenic effect of inflammation, their mechanism of action and their potential as targets for pharmacological intervention remain an area of intense scientific interest. This study investigates the role of a human secreted phospholipase A2 (SPLA2G2A, Group IIA sPLA2, hGIIA), a bifunctional protein involved in the innate immune response and aberrantly expressed in several cancers, in the regulation of lipid droplet (LD) formation within prostate cancer (PCa) cell lines. Lipid metabolism plays a crucial role in cancer progression, particularly in PCa, where LDs serve as an energy source, and a source of fatty acids for rapid membrane synthesis during cell division. High LD levels are linked to resistance to chemotherapy and radiotherapy and correlate with aggressive tumour phenotypes and poor prognosis in PCa. The study further explores the impact of a novel experimental medicine, KM3, on tumour cell lipid metabolism. KM3 selectively targets the established non-catalytic intracellular function of hGIIA, is orally effective in animal models of PCa and is clinically well tolerated in men with advanced PCa.
hGIIA expression and its relationship to LD formation were assessed in PC3, DU145, and LNCaP PCa cell lines using BODIPY staining and immunofluorescence quantification through live cell imaging and fixed cell analysis. The impact of exogenous hGIIA and the selective hGIIA inhibitor peptide KM3 on LD formation was also evaluated, both with and without hGIIA stimulation.
KM3 has been shown to affect hGIIA function by inhibiting its protein-protein interaction with vimentin, inducing apoptosis in all three PCa cell lines. Deletion of vimentin in DU145 cells using CRISPR/Cas9 resulted in loss of KM3’s apoptotic effect. This study examines the effect of vimentin deletion on LD formation and the effect of KM3 on LDs with and without exogenous hGIIA. The impact of these interventions on LD markers (PLIN-2, PLIN-3), lipid metabolism markers (DGAT-1, FASN), and apoptosis markers (Bax, Bcl-2, caspase-9, cytochrome c) will give further insight into the mechanism(s) by which both hGIIA and KM3 modulate lipid metabolism in these cells.
Our findings suggest that hGIIA regulates LD formation and metabolism in PCa cells. Inhibition with KM3 effectively modulates lipid accumulation and impacts downstream metabolic pathways, offering potential therapeutic insights for targeting lipid metabolism in PCa.