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Int J Biochem Cell Biol. 2014 Aug;53:253-61. doi: 10.1016/j.biocel.2014.05.026. Epub 2014 May 28.

Extracellular-signal-regulated kinase 5 modulates the antioxidant response by transcriptionally controlling Sirtuin 1 expression in leukemic cells.

Author information

1
INSERM, U1040, Université de Montpellier 1, UFR Medecine, 80 av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
2
European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille2 University, F-59000 Lille, France.
3
Department of Physiology, Université de Lausanne, Rue du Bugnon 7, CH1005 Lausanne, Switzerland.
4
Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
5
INSERM, U1040, Université de Montpellier 1, UFR Medecine, 80 av. Augustin Fliche, 34295 Montpellier Cedex 5, France; Institut de Recherche en Biothérapie (IRB), CHU Montpellier, 34295 Montpellier, France. Electronic address: martin.villalba@inserm.fr.

Abstract

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.

KEYWORDS:

Anti-oxidant response elements (ARE); ERK5; Mitochondria; Oxidative phosphorylation; Sirt1

PMID:
24880091
DOI:
10.1016/j.biocel.2014.05.026
[Indexed for MEDLINE]

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