| Literature DB >> 35014179 |
Arnaud Blomme1, Coralie Peter1, Ernest Mui2, Giovanny Rodriguez Blanco1, Ning An3, Louise M Mason4, Lauren E Jamieson5, Grace H McGregor1,2, Sergio Lilla1, Chara Ntala1,2, Rachana Patel1, Marc Thiry6, Sonia H Y Kung7,8, Marine Leclercq3, Catriona A Ford1, Linda K Rushworth1,2, David J McGarry1, Susan Mason1, Peter Repiscak1, Colin Nixon1, Mark J Salji2, Elke Markert2, Gillian M MacKay1, Jurre J Kamphorst1,2, Duncan Graham5, Karen Faulds5, Ladan Fazli7,8, Martin E Gleave7,8, Edward Avezov9, Joanne Edwards2, Huabing Yin4, David Sumpton1, Karen Blyth1,2, Pierre Close3, Daniel J Murphy1,2, Sara Zanivan1,2, Hing Y Leung1,2.
Abstract
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.Entities:
Keywords: ATF4; ER stress; lipid metabolism; prostate cancer; therapy resistance
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Year: 2022 PMID： 35014179 PMCID： PMC8899912 DOI： 10.15252/emmm.202114764
Source DB: PubMed Journal: EMBO Mol Med ISSN： 1757-4676 Impact factor: 12.137