Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Blomme, A; Peter, C; Mui, E; Rodriguez, Blanco, G; An, N; Mason, LM; Jamieson, LE; McGregor, GH; Lilla, S; Ntala, C; Patel, R; Thiry, M; Kung, SHY; Leclercq, M; Ford, CA; Rushworth, LK; McGarry, DJ; Mason, S; Repiscak, P; Nixon, C; Salji, MJ; Markert, E; MacKay, GM; Kamphorst, JJ; Graham, D; Faulds, K; Fazli, L; Gleave, ME; Avezov, E; Edwards, J; Yin, H; Sumpton, D; Blyth, K; Close, P; Murphy, DJ; Zanivan, S; Leung, HY.
THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.
EMBO Mol Med. 2022; 14(3): e14764
Doi: 10.15252/emmm.202114764
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- Co-Autor*innen der Med Uni Graz
- Rodriguez Blanco Giovanny
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Androgen Antagonists - pharmacology, therapeutic use
- Gene Expression Regulation, Neoplastic - administration & dosage
- Humans - administration & dosage
- Lipid Metabolism - administration & dosage
- Male - administration & dosage
- Prostatic Neoplasms, Castration-Resistant - drug therapy, pathology
- Find related publications in this database (Keywords)
- ATF4
- ER stress
- lipid metabolism
- prostate cancer
- therapy resistance