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.
|Original language||English (US)|
|Number of pages||9|
|Journal||International Journal of Biochemistry and Cell Biology|
|State||Published - Aug 2014|
Bibliographical noteFunding Information:
This work was supported by the program “Chercheur d’avenir” from the Region Languedoc-Rousillon (MV), a scientific program from the “Communauté de Travail des Pyrénées” (CTPP10/09 to MV), the Association pour la Recherche contre le Cancer (MV), the Fondation pour la Recherche Medicale (MV), l’association CIEL, l’association L’Un pour l’Autre et la fédération Ensangble (MV), a grant FEDER (Fonds européen de développement régional) Objectif competitivite (MV) , a grant CliNK SOE2/P1/E341 from Sudoe/Interreg IV B (EU to MV) and fellowships from La Ligue Contre le Cancer (NL-R) and from the ARC and the Higher Education Commission, Pakistan (MGR).
- Anti-oxidant response elements (ARE)
- Oxidative phosphorylation