Abstract 1152: Lipid elongation: an unexplored therapeutic target in prostate cancer

Abstract

Abstract Dysregulated lipid metabolism is one of the hallmarks of cancer, particularly for prostate cancer (PCa). PCa cells exhibit distinctive metabolic features such as upregulation of enzymes involved in de novo synthesis, uptake and beta-oxidation of lipids, which promote prostate cancer growth, metastasis, and drug resistance. Androgen signalling is a major driver of both PCa growth and lipid metabolism in PCa cells, however the precise effects of androgens on cellular lipid composition and 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 and the enzymes involved in lipid metabolism, and explored the influence of these enzymes on tumour cell behaviour such as cell migration, proliferation and attachment. PCa cell lines (AR positive and negative) were cultured in the absence or presence of androgens or the anti-androgen enzalutamide, and changes in intact phospholipid species were assessed by ESI-MS/MS-based lipidomics. This analysis revealed a complexity of changes in phospholipid profiles 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 critical lipid metabolism pathways 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. The androgenic regulation of ELOVL enzymes was confirmed in clinical PCa cohorts and in primary tumours cultured as explants. Targeting ELOVL gene expression also significantly attenuated the tumorigenic properties of PCa cells. ELOVL downregulation decreased LNCaP cell migration, and adhesion to fibronectin. Furthermore, ELOVL knock down significantly decreased three-dimensional spheroid growth of LNCaP cells using a hang drop assay. The impact of these enzymes on the lipid profile of PCa cell membrane and cell viability, adhesion and migration suggests that they may represent promising and previously unexplored therapeutic targets. Citation Format: Zeyad D. Nassar, Margaret M. Centenera, Jelle Machiels, Samuel J. Polacek, Katarzyna Bloch, Wayne D. Tilley, Luke A. Selth, Johannes V. Swinnen, Lisa Butler. Lipid elongation: an unexplored therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2017-1152