ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer

  • Cancer Res. 2021 Apr 1;81(7):1704-1718. doi: 10.1158/0008-5472.CAN-20-2511.
Margaret M Centenera  1  2  3 ,  Julia S Scott  1  2  3 ,  Jelle Machiels  4 ,  Zeyad D Nassar  1  2  3 ,  Deanna C Miller  1  2  3 ,  Irene Zinonos  1  5 ,  Jonas Dehairs  4 ,  Ingrid J G Burvenich  6  7 ,  Giorgia Zadra  8 ,  Paolo M Chetta  8  9 ,  Clyde Bango  8 ,  Emma Evergren  10 ,  Natalie K Ryan  1  3 ,  Joanna L Gillis  1  3 ,  Chui Yan Mah  1  2  3 ,  Terence Tieu  11  12 ,  Adrienne R Hanson  1 ,  Ryan Carelli  13 ,  Katarzyna Bloch  4 ,  Vasilios Panagopoulos  1  3 ,  Etienne Waelkens  14 ,  Rita Derua  14 ,  Elizabeth D Williams  15 ,  Andreas Evdokiou  1  5 ,  Anna Cifuentes-Rius  11 ,  Nicolas H Voelcker  11  12  16 ,  Ian G Mills  10  17 ,  Wayne D Tilley  1  2 ,  Andrew M Scott  6  7  18  19 ,  Massimo Loda  13 ,  Luke A Selth  1  2  20 ,  Johannes V Swinnen  #  21 ,  Lisa M Butler  #  22  2  3
Affiliations
  • 1. University of Adelaide Medical School, Adelaide, SA, Australia.
  • 2. Freemasons Foundation Centre for Men's Health, Adelaide, SA, Australia.
  • 3. South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
  • 4. Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven, Belgium.
  • 5. Basil Hetzel Institute, Queen Elizabeth Hospital, SA, Australia.
  • 6. Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
  • 7. School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
  • 8. Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 9. University of Milan, Milan, Italy.
  • 10. Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
  • 11. Drug Delivery, Disposition and Dynamics, Monash University, Parkville, VIC, Australia.
  • 12. Commonwealth Scientific and Industrial Research Organisation (CSIRO), Clayton, VIC, Australia.
  • 13. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York.
  • 14. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • 15. Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology (QUT), Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD, Australia.
  • 16. Melbourne Centre for Nanofabrication, Victorian Node of the Australian National Fabrication Facility, Clayton, VIC, Australia.
  • 17. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
  • 18. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
  • 19. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia.
  • 20. Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia.
  • 21. Department of Oncology, Laboratory of Lipid Metabolism and Cancer, KU Leuven, Leuven, Belgium. [email protected] [email protected].
  • 22. University of Adelaide Medical School, Adelaide, SA, Australia. [email protected] [email protected].
  • # Contributed equally.
PMID: 33547161 DOI: 10.1158/0008-5472.CAN-20-2511
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. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.