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

Rathore, M. G.; Saumet, A.; Rossi, J. F.; de Bettignies, C.; Tempe, D.; Lecellier, C. H.; Villalba, M.

Int J Biochem Cell Biol

2012-09 / vol 44 / pages 1448-56


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-kappaB 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-kappaB 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.

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Cell Line, Tumor; Humans; Animals; Mice; Base Sequence; Cell Proliferation/drug effects; Genes, Reporter/genetics; Cell Cycle Checkpoints/drug effects/genetics; Cell Death/drug effects/genetics; Down-Regulation/drug effects/genetics; Glutaminase/metabolism; Glutamine/*metabolism/pharmacology; Histone Deacetylases/metabolism; Luciferases/genetics; MicroRNAs/*genetics/*metabolism; Mitochondria/drug effects/metabolism; Promoter Regions, Genetic/drug effects/genetics; Transcription Factor RelA/*metabolism; Transcription, Genetic/drug effects/genetics

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