2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer.

Abstract

Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.

• Authors: Arnaud Blomme, Catriona A Ford, Ernest Mui, Rachana Patel, Chara Ntala, Lauren E Jamieson, Mélanie Planque, Grace H McGregor, Paul Peixoto, Eric Hervouet, Colin Nixon, Mark Salji, Luke Gaughan, Elke Markert, Peter Repiscak, David Sumpton, Giovanny Rodriguez Blanco, Sergio Lilla, Jurre J Kamphorst, Duncan Graham, Karen Faulds, Gillian M MacKay, Sarah-Maria Fendt, Sara Zanivan, Hing Y Leung
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2508 (05 19 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32427840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Receptor Antagonists
• Phospholipids
• Receptors, Androgen
• Oxidoreductases Acting on CH-CH Group Donors
• 2,4-dienoyl-CoA reductase

Topics

• Androgen Receptor Antagonists (administration & dosage)
• Disease Progression
• Homeostasis
• Humans
• Lipid Metabolism
• Male
• Mitochondria (enzymology, genetics)
• Oxidoreductases Acting on CH-CH Group Donors (genetics, metabolism)
• Phospholipids (metabolism)
• Prostate (enzymology, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, enzymology, genetics)
• Receptors, Androgen (genetics, metabolism)