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SHR Neuro Cancer Cardio Lipid Metab Microb
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, SM; Zanivan, S; Leung, HY.
2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer.
Nat Commun. 2020; 11(1):2508
Doi: 10.1038/s41467-020-16126-7
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- Co-authors Med Uni Graz
- Rodriguez Blanco Giovanny
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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.
- Find related publications in this database (using NLM MeSH Indexing)
- Androgen Receptor Antagonists - administration & dosage
- Disease Progression - administration & dosage
- Homeostasis - administration & dosage
- Humans - administration & dosage
- Lipid Metabolism - administration & dosage
- Male - administration & dosage
- Mitochondria - enzymology, genetics
- Oxidoreductases Acting on CH-CH Group Donors - genetics, metabolism
- Phospholipids - metabolism
- Prostate - enzymology, metabolism
- Prostatic Neoplasms, Castration-Resistant - drug therapy, enzymology, genetics
- Receptors, Androgen - genetics, metabolism