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

Blomme, Arnaud and Ford, Catriona A. and Mui, Ernest and Patel, Rachana and Ntala, Chara and Jamieson, Lauren E. and Planque, Mélanie and McGregor, Grace H. and Peixoto, Paul and Hervouet, Eric and Nixon, Colin and Salji, Mark and Gaughan, Luke and Markert, Elke and Repiscak, Peter and Sumpton, David and Blanco, Giovanny Rodriguez and Lilla, Sergio and Kamphorst, Jurre J. and Graham, Duncan and Faulds, Karen and MacKay, Gillian M. and Fendt, Sarah-Maria and Zanivan, Sara and Leung, Hing Y. (2020) 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nature Communications, 11. 2508. ISSN 2041-1723 (https://doi.org/10.1038/s41467-020-16126-7)

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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.

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