期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 53, 期 -, 页码 253-261出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2014.05.026
关键词
Oxidative phosphorylation; Mitochondria; ERK5; Sirt1; Anti-oxidant response elements (ARE)
资金
- program Chercheur d'avenir from the Region Languedoc-Rousillon
- scientific program from the Communaute de Travail des Pyrenees [CTPP10/09]
- Fondation pour la Recherche Medicale
- l'association CIEL
- l'association L'Un pour l'Autre et la federation Ensangble
- FEDER (Fonds europeen de developpement regional) Objectif competitivite
- Sudoe/Interreg IV B [CliNK SOE2/P1/E341]
- La Ligue Contre le Cancer (NL-R)
- ARC
- Higher Education Commission, Pakistan
Cancer cell metabolism differs from that of non-transformed cells in the same tissue. This specific metabolism gives tumor cells growing advantages besides the effect in increasing anabolism. One of these advantages is immune evasion mediated by a lower expression of the mayor histocompatibility complex class I molecules. The extracellular-signal-regulated kinase-5 regulates both mayor histocompatibility complex class I expression and metabolic activity. However, the mechanisms underlying are largely unknown. We show here that extracellular-signal-regulated kinase-5 regulates the transcription of the NADH(+)-dependent histone deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin 1) in leukemic Jurkat T cells. This involves the activation of the transcription factor myocyte enhancer factor-2 and its binding to the sirt1 promoter. In addition, extracellular-signal-regulated kinase-5 is required for T cell receptor-induced and oxidative stress-induced full Sirtuin 1 expression. Extracellular-signal-regulated kinase-5 induces the expression of promoters containing the antioxidant response elements through a Sirtuin 1-dependent pathway. On the other hand, down modulation of extracellular-signal-regulated kinase-5 expression impairs the anti-oxidant response. Notably, the extracellular-signal-regulated kinase-5 inhibitor BIX02189 induces apoptosis in acute myeloid leukemia tumor cells without affecting T cells from healthy donors. Our results unveil a new pathway that modulates metabolism in tumor cells. This pathway represents a promising therapeutic target in cancers with deep metabolic layouts such as acute myeloid leukemia. (C) 2014 Elsevier Ltd. All rights reserved.
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