Regulation of autophagy by NFkappaB transcription factor and reactives oxygen species.

The NFkB transcription factor is an important anti-apoptotic factor, which is frequently deregulated in cancer cells. We have recently demonstrated that NFkB activation mediates the repression of autophagy in response to TNFa in three models of cancer cell lines. In contrast, in the absence of NFkB activation, TNFa induces macroautophagy (autophagy), which requires reactive oxygen species (ROS) production and participates in the TNFa- induced apoptotic signaling pathway. Autophagy-dependent apoptosis was also observed following direct addition of ROS to cells. Moreover, addition of rapamycin to TNFa 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 NFkB 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 NFkB -dependent chemoresistance of cancer cells.