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

Blomme, A. et al. (2020) 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nature Communications, 11, 2508. (doi: 10.1038/s41467-020-16126-7) (PMID:32427840) (PMCID:PMC7237503)

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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.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK Beatson Institute core funding (C596/A17196) and CRUK core group awarded to HYL (A15151) and to SZ (A12935). P.P. and E.H. were funded by grants from “La ligue Contre le Cancer”, “la région Bourgogne Franche-Comté” and “Canceropole Grand Est”. M.S. is a Medical Research Council Clinical Research Fellow (MR/L017997/1). C.N. is the recipient of CRUK Clinical Research Fellowship (grant 300444-01). D.G. and K.F. acknowledge support from the EPSRC grant EP/L014165/1 that supported L.J. S.-M.F. acknowledges FWO funding and KU Leuven Methusalem co-funding.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Lilla, Dr Sergio and Markert, Dr Elke and Leung, Professor Hing and Zanivan, Professor Sara Rossana and Repiscak, Dr Peter and Mui, Mr Ernest and Salji, Dr Mark and Sumpton, Mr David and Ntala, Dr Chara and Mackay, Dr Gillian and Patel, Dr Rachana and McGregor, Grace and Kamphorst, Dr Jurre
Authors: Blomme, A., Ford, C. A., Mui, E., Patel, R., Ntala, C., Jamieson, L. E., Planque, M., McGregor, G., Peixoto, P., Hervouet, E., Nixon, C., Salji, M., Gaughan, L., Markert, E., Repiscak, P., Sumpton, D., Blanco, G. R., Lilla, S., Kamphorst, J. J., Graham, D., Faulds, K., Mackay, G. M., Fendt, S.-M., Zanivan, S. R., and Leung, H. Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © The Author(s) 2020
First Published:First published in Nature Communications 11:2508
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170128Quantitative proteomic analysis of castrate-resistant prostate cancerHing LeungMedical Research Council (MRC)MR/L017997/1Institute of Cancer Sciences
190739In Situ Nanoparticle Assemblies for Healthcare Diagnostics and Therapy. Reference: 130479Pasquale MaffiaEngineering and Physical Sciences Research Council (EPSRC)EP/L014165/1III - Immunology