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NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy.

Abstract : Activation of NF-kappaB and autophagy are two processes involved in the regulation of cell death, but the possible cross-talk between these two signaling pathways is largely unknown. Here, we show that NF-kappaB activation mediates repression of autophagy in tumor necrosis factor-alpha (TNFalpha)-treated Ewing sarcoma cells. This repression is associated with an NF-kappaB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-kappaB activation, TNFalpha 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-kappaB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFalpha- and reactive oxygen species-induced apoptosis in cells lacking NF-kappaB activation and in NF-kappaB-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-kappaB 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-kappaB.
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Contributor : Patrice Codogno Connect in order to contact the contributor
Submitted on : Friday, September 14, 2007 - 11:39:25 AM
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Mojgan Djavaheri-Mergny, Manuela Amelotti, Julie Mathieu, Françoise Besançon, Chantal Bauvy, et al.. NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2006, 281 (41), pp.30373-82. ⟨10.1074/jbc.M602097200⟩. ⟨inserm-00172128⟩



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