University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Jonas Dehairs
KU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
Ingrid JG Burvenich
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, Australia
Swati Irani
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Margaret M Centenera
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Madison Helm
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Raj K Shrestha
Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia
Max Moldovan
South Australian Health and Medical Research Institute, Adelaide, Australia
Anthony S Don
NHMRC Clinical Trials Centre, and Centenary Institute, The University of Sydney, Camperdown, Australia
Jeff Holst
Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, Australia
Andrew M Scott
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, Australia
Lisa G Horvath
Garvan Institute of Medical Research, NSW 2010; University of Sydney, NSW 2006; and University of New South Wales, Darlinghurst, Australia
David J Lynn
South Australian Health and Medical Research Institute, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, Australia
Luke A Selth
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, Australia
Andrew J Hoy
Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia
Johannes V Swinnen
KU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
