ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
Abstract
The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry–based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 05, 2021
- Source ID
- 10.1158/0008-5472.can-20-2511
Entities
People
- Adrienne R. Hanson
- Andreas Evdokiou
- Anna Cifuentes-Rius
- Chui Yan Mah
- Clyde Bango
- Deanna C. Miller
- Elizabeth D. Williams
- Emma Evergren
- Etienne Waelkens
- Giorgia Zadra
- Ian G Mills
- Ingrid Burvenich
- Irene Zinonos
- Jelle Machiels
- Joanna L. Gillis
- Johannes V. Swinnen
- Jonas Dehairs
- Julia S Scott
- Katarzyna Bloch
- Lisa M Butler
- Luke A. Selth
- Margaret M. Centenera
- Massimo Loda
- Natalie K. Ryan
- Nicolas H. Voelcker
- Paolo M. Chetta
- Rita Derua
- Ryan Carelli
- Terence Tieu
- Vasilios Panagopoulos
- Wayne D Tilley
- Zeyad D Nassar
Organizations
- Austin Hospital, Melbourne
- Australian Government
- Cancer Council SA
- Commonwealth Scientific and Industrial Research Organisation
- Dana–Farber Cancer Institute
- Flinders University
- Interreg
- Katholieke Universiteit Leuven
- La Trobe University
- Monash University
- Movember Foundation
- National Cancer Institute
- National Health and Medical Research Council
- National Institutes of Health
- Prostate Cancer Foundation
- Prostate Cancer Foundation of Australia
- Queen's University Belfast
- Queensland University of Technology
- Research Foundation - Flanders
- The Queen Elizabeth Hospital
- United States Department of Defense
- University of Melbourne
- University of Oxford
- Weill Cornell Medicine