title: Extracellular-signal-regulated kinase 5 modulates the antioxidant response by transcriptionally controlling Sirtuin 1 expression in leukemic cells.
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.
authors.affiliation: INSERM, U1040, Université de Montpellier 1, UFR Medecine, 80 av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Royuela
authors.affiliation: INSERM, U1040, Université de Montpellier 1, UFR Medecine, 80 av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors.forename: Moeez G
authors.initials: MG
authors.lastname: Rathore
authors.affiliation: INSERM, U1040, Université de Montpellier 1, UFR Medecine, 80 av. Augustin Fliche, 34295 Montpellier Cedex 5, France.
authors.forename: Nerea
authors.initials: N
authors.lastname: Allende-Vega
authors.affiliation: European Genomic Institute for Diabetes (EGID), CNRS UMR 8199, Lille2 University, F-59000 Lille, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Annicotte
authors.affiliation: Department of Physiology, Université de Lausanne, Rue du Bugnon 7, CH1005 Lausanne, Switzerland.
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Ramachandran
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Tod
authors.initials: T
authors.lastname: Gulick
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Villalba
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics*; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D056564:Sirtuin 1 / Q000096:biosynthesis*
chemical_list: D000975:Antioxidants; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7; D056564:Sirtuin 1
keywords: Anti-oxidant response elements (ARE); ERK5; Mitochondria; Oxidative phosphorylation; Sirt1