THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.

Autor: Blomme A; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Peter C; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Mui E; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Rodriguez Blanco G; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., An N; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., Mason LM; School of Engineering, University of Glasgow, Glasgow, UK., Jamieson LE; Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, UK., McGregor GH; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Lilla S; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Ntala C; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Patel R; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Thiry M; GIGA-Neurosciences, Unit of Cell and Tissue Biology, University of Liège, Liège, Belgium., Kung SHY; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, Vancouver, BC, Canada., Leclercq M; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., Ford CA; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Rushworth LK; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., McGarry DJ; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Mason S; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Repiscak P; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Nixon C; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Salji MJ; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Markert E; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., MacKay GM; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Kamphorst JJ; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Graham D; Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, UK., Faulds K; Centre for Molecular Nanometrology, Department of Pure and Applied Chemistry, Technology and Innovation Centre, University of Strathclyde, Glasgow, UK., Fazli L; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, Vancouver, BC, Canada., Gleave ME; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, Vancouver, BC, Canada., Avezov E; UK Dementia Research Institute at University of Cambridge, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK., Edwards J; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Yin H; School of Engineering, University of Glasgow, Glasgow, UK., Sumpton D; CRUK Beatson Institute, Garscube Estate, Glasgow, UK., Blyth K; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Close P; Laboratory of Cancer Signaling, GIGA-Institute, University of Liège, Liège, Belgium., Murphy DJ; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Zanivan S; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK., Leung HY; CRUK Beatson Institute, Garscube Estate, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2022 Mar 07; Vol. 14 (3), pp. e14764. Date of Electronic Publication: 2022 Jan 11.
DOI: 10.15252/emmm.202114764
Abstrakt: Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.
(© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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