TY - JOUR
T1 - NF-κB activation represses tumor necrosis factor-α-induced autophagy
AU - Djavaheri-Mergny, Mojgan
AU - Amelotti, Manuela
AU - Mathieu, Julie
AU - Besançon, Françoise
AU - Bauvy, Chantal
AU - Souquère, Sylvie
AU - Pierron, Gérard
AU - Codogno, Patrice
PY - 2006/10/13
Y1 - 2006/10/13
N2 - Activation of NF-κB 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-κB activation mediates repression of autophagy in tumor necrosis factor-α (TNFα)-treated Ewing sarcoma cells. This repression is associated with an NF-κB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-κB activation, TNFα 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-κB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFα- and reactive oxygen species-induced apoptosis in cells lacking NF-κB activation and in NF-κB-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-κB 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-κB.
AB - Activation of NF-κB 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-κB activation mediates repression of autophagy in tumor necrosis factor-α (TNFα)-treated Ewing sarcoma cells. This repression is associated with an NF-κB-dependent activation of the autophagy inhibitor mTOR. In contrast, in cells lacking NF-κB activation, TNFα 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-κB-competent cells by the addition of H2O2. Small interfering RNA-mediated knockdown of beclin 1 and atg7 expression, two autophagy-related genes, reduced TNFα- and reactive oxygen species-induced apoptosis in cells lacking NF-κB activation and in NF-κB-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-κB 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-κB.
UR - http://www.scopus.com/inward/record.url?scp=33750071414&partnerID=8YFLogxK
U2 - 10.1074/jbc.M602097200
DO - 10.1074/jbc.M602097200
M3 - Article
C2 - 16857678
AN - SCOPUS:33750071414
SN - 0021-9258
VL - 281
SP - 30373
EP - 30382
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -