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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidant Response Elements / genetics*
  • Antioxidants / metabolism*
  • Apoptosis / genetics
  • Gene Expression Regulation, Leukemic
  • Humans
  • Jurkat Cells
  • Leukemia / genetics*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitogen-Activated Protein Kinase 7 / biosynthesis
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Oxidative Phosphorylation
  • Signal Transduction / genetics
  • Sirtuin 1 / biosynthesis*

Substances

  • Antioxidants
  • MAPK7 protein, human
  • Mitogen-Activated Protein Kinase 7
  • Sirtuin 1