Poster Presentation 2nd Australian Cancer and Metabolism Meeting 2017

Lipid elongation: an unexplored therapeutic target in prostate cancer? (#59)

Zeyad Nassar 1 , Maggie Centenera 1 , Jelle Machiels 2 , Wayne Tilley 3 , Luke Selth 3 , Johan Swinnen 2 , Lisa Butler 1
  1. University of Adelaide, Adelaide, SA, Australia
  2. Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven, Belgium
  3. Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide, Hanson Institute, Adelaide, South Australia

Dysregulated lipid metabolism is one of the hallmarks of cancer, particularly for prostate cancer (PCa). Androgen signalling is a major driver of both PCa growth and lipid metabolism in PCa cells, however, the molecular pathways by which androgens regulate lipid metabolism in PCa cells are yet to be elucidated. In this study, we investigated the effect of androgens on the lipid composition of PCa cell membranes, the enzymes involved in lipid metabolism, and their influence on tumour cell behaviour. PCa cell lines (AR positive and negative) were cultured in the absence or presence of androgens or the anti-androgen enzalutamide, and changes in phospholipid species assessed by ESI-MS/MS-based lipidomics. This analysis revealed a complexity of lipidomic changes in response to androgen treatment. Strikingly, elongation of the fatty acyl chains was consistently observed for multiple phospholipid classes in response to the androgens mibolerone or 5α-dihydotestosterone, whereas inhibition of elongation was observed in the presence of enzalutamide. Transcriptional analysis of lipid metabolic enzymes revealed that the enzymes that catalyse lipid elongation (ELOVLs) were markedly induced by androgens in multiple PCa cell lines, and siRNA depletion of these enzymes, either alone or in combination, reversed the androgen-induced fatty acyl elongation phenotype. Androgenic regulation of ELOVL enzymes was confirmed in clinical PCa and in primary tumours cultured as explants. Targeting ELOVL gene expression significantly attenuated LNCaP cell viability, migration, adhesion to fibronectin and three-dimensional spheroid growth. The impact of these enzymes on the lipid profile of PCa cell membranes and key tumorigenic properties suggests that they may represent promising and previously unexplored therapeutic targets.