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; Hing Y. Leung

doi:10.1038/s41467-020-16126-7

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 GrahamKaren Faulds, Gillian M. MacKay, Sarah-Maria Fendt, Sara Zanivan, Hing Y. Leung^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	2508
Number of pages	17
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-16126-7
Publication status	Published - 19 May 2020

Funding

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.

Keywords

androgen receptor
AR signalling
castration-resistant prostate cancer
LNCaP cells
AR inhibitors

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Blomme, A., Ford, C. A., Mui, E., Patel, R., Ntala, C., Jamieson, L. E., Planque, M., McGregor, G. H., Peixoto, P., Hervouet, E., Nixon, C., Salji, M., Gaughan, L., Markert, E., Repiscak, P., Sumpton, D., Blanco, G. R., Lilla, S., Kamphorst, J. J., ... Leung, H. Y. (2020). 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer. Nature Communications, 11, Article 2508. https://doi.org/10.1038/s41467-020-16126-7

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title = "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.",

keywords = "androgen receptor, AR signalling, castration-resistant prostate cancer, LNCaP cells, AR inhibitors",

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doi = "10.1038/s41467-020-16126-7",

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Blomme, A, Ford, CA, Mui, E, Patel, R, Ntala, C, Jamieson, LE, Planque, M, McGregor, GH, Peixoto, P, Hervouet, E, Nixon, C, Salji, M, Gaughan, L, Markert, E, Repiscak, P, Sumpton, D, Blanco, GR, Lilla, S, Kamphorst, JJ, Graham, D , Faulds, K, MacKay, GM, Fendt, S-M, Zanivan, S & Leung, HY 2020, '2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer', Nature Communications, vol. 11, 2508. https://doi.org/10.1038/s41467-020-16126-7

TY - JOUR

T1 - 2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer

AU - Blomme, Arnaud

AU - Ford, Catriona A.

AU - Mui, Ernest

AU - Patel, Rachana

AU - Ntala, Chara

AU - Jamieson, Lauren E.

AU - Planque, Mélanie

AU - McGregor, Grace H.

AU - Peixoto, Paul

AU - Hervouet, Eric

AU - Nixon, Colin

AU - Salji, Mark

AU - Gaughan, Luke

AU - Markert, Elke

AU - Repiscak, Peter

AU - Sumpton, David

AU - Blanco, Giovanny Rodriguez

AU - Lilla, Sergio

AU - Kamphorst, Jurre J.

AU - Graham, Duncan

AU - Faulds, Karen

AU - MacKay, Gillian M.

AU - Fendt, Sarah-Maria

AU - Zanivan, Sara

AU - Leung, Hing Y.

PY - 2020/5/19

Y1 - 2020/5/19

N2 - 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.

AB - 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.

KW - androgen receptor

KW - AR signalling

KW - castration-resistant prostate cancer

KW - LNCaP cells

KW - AR inhibitors

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U2 - 10.1038/s41467-020-16126-7

DO - 10.1038/s41467-020-16126-7

M3 - Article

C2 - 32427840

AN - SCOPUS:85084962130

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 2508

ER -

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

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