The NF-κB member p65 controls glutamine metabolism through miR-23a

Moeez G. Rathore, Anne Saumet, Jean François Rossi, Carine De Bettignies, Denis Tempé, Charles Henri Lecellier, Martin Villalba

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Cancer cells have elevated aerobic glycolysis that is termed the Warburg effect. But several tumor cells, including leukemic cells, also increase glutamine metabolism, which is initiated by glutaminase (GLS). The microRNA (miRNA) miR-23 targets GLS mRNA and inhibits expression of GLS protein. Here we show that in human leukemic Jurkat cells the NF-κB p65 subunit binds to miR-23a promoter and inhibits miR-23a expression. Histone deacetylase (HDAC) inhibitors release p65-induced inhibition. Jurkat cells growing in glutamine decrease proliferation due to cell accumulation in G0/G1 phase. Nevertheless, cells get used to this new source of energy by increasing GLS expression, which correlates with an increase in p65 expression and its translocation to the nucleus, leading to a higher basal NF-κB activity. Jurkat cells overexpressing p65 show increase basal GLS expression and proliferate faster than control cells in glutamine medium. Overexpressing miR-23a in leukemic cells impaired glutamine use and induces mitochondrial dysfunction leading to cell death. Therefore, p65 activation decreases miR-23a expression, which facilitates glutamine consumption allowing leukemic cells to use this alternative source of carbon and favoring their adaptation to the metabolic environment.

Original languageEnglish (US)
Pages (from-to)1448-1456
Number of pages9
JournalInternational Journal of Biochemistry and Cell Biology
Volume44
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Bibliographical note

Funding 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), a grant FEDER Objectif competitivite (MV), a grant from European Community Program SUDOE (MV) and a fellowships from the ARC and Higher Education Commission, Pakistan (MGR).

Keywords

  • Glutaminase
  • Metabolism
  • Mitochondria
  • NF-κB
  • Warburg effect
  • microRNA-23

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