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

Activation of NF-kappa B 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-kappa B activation mediates repression of autophagy in tumor necrosis factor-alpha (TNF alpha)-treated Ewing sarcoma cells. This repression is associated with an NF-kappa B-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-kappa B activation, TNF alpha 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-kappa B-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNF alpha- and reactive oxygen species-induced apoptosis in cells lacking NF-kappa B activation and in NF-kappa B-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-kappa B 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-kappa B.