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

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 and Hing Y. Leung ()
Additional contact information
Arnaud Blomme: Garscube Estate
Catriona A. Ford: Garscube Estate
Ernest Mui: University of Glasgow, Garscube Estate
Rachana Patel: Garscube Estate
Chara Ntala: Garscube Estate
Lauren E. Jamieson: University of Strathclyde
Mélanie Planque: VIB-KU Leuven Center for Cancer Biology
Grace H. McGregor: Garscube Estate
Paul Peixoto: Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique
Eric Hervouet: Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique
Colin Nixon: Garscube Estate
Mark Salji: University of Glasgow, Garscube Estate
Luke Gaughan: Newcastle University
Elke Markert: University of Glasgow, Garscube Estate
Peter Repiscak: Garscube Estate
David Sumpton: Garscube Estate
Giovanny Rodriguez Blanco: Garscube Estate
Sergio Lilla: Garscube Estate
Jurre J. Kamphorst: Garscube Estate
Duncan Graham: University of Strathclyde
Karen Faulds: University of Strathclyde
Gillian M. MacKay: Garscube Estate
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology
Sara Zanivan: Garscube Estate
Hing Y. Leung: Garscube Estate

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16126-7

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