NF-κB activation represses tumor necrosis factor-α-induced autophagy

Mojgan Djavaheri-Mergny, Manuela Amelotti, Julie Mathieu, Françoise Besançon, Chantal Bauvy, Sylvie Souquère, Gérard Pierron, Patrice Codogno

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

421 Citations (Scopus)

Résumé

Activation of NF-κB and autophagy are two processes involved in the regulation of cell death, but the possible crosstalk between these two signaling pathways is largely unknown. Here, we show that NF-κB activation mediates repression of autophagy in tumor necrosis factor-α (TNFα)-treated Ewing sarcoma cells. This repression is associated with an NF-κB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-κB activation, TNFα treatment up-regulates the expression of the autophagy-promoting protein Beclin 1 and subsequently induces the accumulation of autophagic vacuoles. Both of these responses are dependent on reactive oxygen species (ROS) production and can be mimicked in NF-κB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFα- and reactive oxygen species-induced apoptosis in cells lacking NF-κB activation and in NF-κB-competent cells, respectively. These findings demonstrate that autophagy may amplify apoptosis when associated with a death signaling pathway. They are also evidence that inhibition of autophagy is a novel mechanism of the antiapoptotic function of NF-κB activation. We suggest that stimulation of autophagy may be a potential way bypassing the resistance of cancer cells to anti-cancer agents that activate NF-κB.

langue originaleAnglais
Pages (de - à)30373-30382
Nombre de pages10
journalJournal of Biological Chemistry
Volume281
Numéro de publication41
Les DOIs
étatPublié - 13 oct. 2006
Modification externeOui

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