NF-κB activation represses tumor necrosis factor-α-induced autophagy
NF-κB activation represses tumor necrosis factor-α-induced autophagy
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DOI：
10.1074/jbc.m602097200
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发表时间：
2006-10-13
影响因子：
4.8
通讯作者：
Codogno, Patrice
中科院分区：
文献类型：
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作者：
Djavaheri-Mergny, Mojgan;Amelotti, Manuela;Codogno, Patrice
NF-κ B的激活和自噬是参与细胞死亡调节的两个过程，但这两个信号通路之间可能的串扰在很大程度上是未知的。在这里，我们表明，NF-κ B B激活介导抑制肿瘤坏死因子-α（TNF-α）处理的尤文肉瘤细胞的自噬。这种抑制与自噬抑制剂mTOR的NF-κ B依赖性活化相关。相反，在缺乏NF-κ B活化的细胞中，TNF α处理上调自噬促进蛋白Beclin 1的表达，随后诱导自噬空泡的积累。这两种反应都依赖于活性氧（ROS）的产生，并且可以通过加入H2 O2在NF-κ B感受态细胞中模拟。小干扰RNA介导的beclin 1和atg 7表达的敲低，两个自噬相关基因，分别减少了缺乏NF-κ B B活化的细胞和NF-κ B感受态细胞中TNF α和活性氧诱导的细胞凋亡。这些发现表明，自噬可能会放大细胞凋亡时，与死亡信号通路。它们也证明了抑制自噬是NF-κ B激活的抗凋亡功能的新机制。我们认为，刺激自噬可能是绕过癌细胞对激活NF-κ B的抗癌药物的抗性的一种潜在途径。
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.