Poster Presentation Hunter Cell Biology Meeting 2025

The innate immune mediator group IIA secreted phospholipase A2 modulates lipid droplet formation in prostate cancer cells. (#200)

Monavvar Andarva 1 , Maria George Elias 1 , Timothy J Mann 2 , Mila Sajinovic 3 , Tanzila Khan 3 , Tara L Roberts 1 , Paul De Souza 4 , Kieran F Scott 1
  1. School of Medicine, Western Sydney University, Campbelltown, New South Wales 2560, Australia
  2. Faculty of Medicine, University of New South Wales, Kensington, NSW 2033, Australia
  3. Medical Oncology, Ingham Institute of Applied Medical research, Liverpool, New South Wales 2170, Australia
  4. Nepean Hospital Clinical School, University of Sydney, Kingswood, New South Wales 2747, Australia

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-tumorigenic 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 the innate immune regulator, human secreted phospholipase A2 (SPLA2G2A, Group IIA sPLA2, hGIIA) on lipid droplet (LD) formation in prostate cancer cells. hGIIA is aberrantly expressed in many inflammatory conditions including cancer. Lipid droplets, once regarded as passive lipid reservoirs, are now recognized as active regulators of inflammation. hGIIA is a bifunctional protein that acts as a phospholipid hydrolysing enzyme in the high calcium extracellular environment. On internalisation, hGIIA selectively binds the intermediate filament protein vimentin which acts as a scaffold for lipid droplets. Therefore, it is possible that hGIIA may regulate lipid droplet formation in prostate cancer cells thereby modulating cancer cell energy metabolism. 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.This study further explores the impact of a novel experimental medicine, c2, on tumour cell lipid metabolism. c2 selectively blocks the hGIIA- vimentin interaction is orally effective in animal models of PCa and is clinically well tolerated in men with advanced PCa.

hGIIA’s role in LD formation was assessed in prostate cancer cell lines via immunofluorescence analysis in live and fixed cells. The impact on LDs of increasing hGIIA (via exogenous addition) or its inhibition (via c2 treatment) was also analysed. This study also examines the effect of CRISPR/Cas9-mediated vimentin deletion on LD formation and the effect of c2 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 (Pro caspase-3, cytochrome c) will give further insight into the mechanism(s) by which both hGIIA and c2 modulate lipid metabolism in these cells.

Our findings suggest that the inflammatory mediator hGIIA regulates LD formation and metabolism in PCa cells. Inhibition with c2 modulates lipid accumulation and may impact downstream metabolic pathways, offering potential therapeutic insights for targeting lipid metabolism in PCa.