Regulation of autophagy by NFκB transcription factor and reactives oxygen species

The NFicB transcription factor is an important anti-apoptotic factor, which is frequently deregulated in cancer cells. We have recently demonstrated that NFxB activation mediates the repression of autophagy in response to TNF alpha in three models of cancer cell lines. In contrast, in the absence of NF kappa B activation TNF alpha induces macroautophagy (autophagy), which requires reactive oxygen species (ROS) production and participates in the TNF alpha-induced apoptotic signaling pathways. Autophagy-dependent apoptosis was also observed following direct addition of ROS to cells. Moreover, addition of rapamycin to TNF alpha renders these cells susceptible to the cytotoxic effect of this cytokine. These findings highlight the regulation of autophagy by oxidative stress and support the idea that repression of autophagy by NF kappa B may constitute a novel anti-apoptotic function of this transcription factor. We also bring evidence that direct stimulation of autophagy may represent a new therapeutic strategy for overcoming the NF kappa B-dependent chemoresistance of cancer cells.