Regulation of autophagy by NFkappaB transcription factor and reactives oxygen species.
The NF-kappaB transcription factor is an important anti-apoptotic factor, which is frequently deregulated in cancer cells. We have recently demonstrated that NF-kappaB activation mediates the repression of autophagy in response to TNFa in three models of cancer cell lines. In contrast, in the absence of NF-kappaB activation, TNFa induces macroautophagy (autophagy), which requires reactive oxygen species (ROS) production and participates in the TNFalpha-induced apoptotic signaling pathway. Autophagy-dependent apoptosis was also observed following direct addition of ROS to cells. Moreover, addition of rapamycin to TNFalpha 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-kappaB 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-kappaB-dependent chemoresistance of cancer cells.
Djavaheri-Mergny
Mojgan
M
INSERM U756, Châtenay-Malabry, France. mojgan.mergny@u-psud.fr
Amelotti
Manuella
M
Mathieu
Julie
J
Besançon
Francoise
F
Bauvy
Chantal
C
Codogno
Patrice
P
D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha