Journal Article

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

Gaughan, Luke, 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, Kamphorst, Jurre, J, Hervouet, Eric, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC) ; Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comt

2020

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/89 / 42/41 / 45/77 / 49/15 / 631/45/320 / 631/45/475 / 631/45/608 / 631/67/2327 / 631/67/589/466 / 82/58 / 96/95 / Activation / Androgen Receptor Antagonists - administration & dosage / Androgen receptors / Androgens / Biochemistry, biophysics & molecular biology / Biochimie, biophysique & biologie moléculaire / Biomarkers / Cancer / Castration / Cellular Biology / Disease Progression / Ferroptosis / Glucose / Glucose metabolism / Homeostasis / Humanities and Social Sciences / Humans / Life Sciences / Lipid Metabolism / Lipids / Male / Metabolism / Metabolomics / Mitochondria / Mitochondria - enzymology / Mitochondria - genetics / multidisciplinary / Oxidation / Oxidoreductases Acting on CH-CH Group Donors - genetics / Oxidoreductases Acting on CH-CH Group Donors - metabolism / Phenotypes / Phospholipids / Phospholipids - metabolism / Prostate - enzymology / Prostate - metabolism / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - enzymology / Prostatic Neoplasms, Castration-Resistant - genetics / Proteomics / Receptors / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Reductase / Reductases / Rewiring / Science / Science (multidisciplinary) / Sciences du vivant / Signaling / Treatment resistance / Tumors