Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy
Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy
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DOI：
10.4161/auto.9099
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发表时间：
2009-08-16
期刊：
影响因子：
13.3
通讯作者：
Shen, Han-Ming
中科院分区：
文献类型：
--
作者：
Wu, You-Tong;Tan, Hui-Ling;Shen, Han-Ming
我们先前的工作已经表明，自噬在两种坏死细胞死亡模型中起促存活作用：zVAD处理的L929细胞以及H2 O2处理的Bax（-/-）巴克（-/-）小鼠胚胎成纤维细胞（DKO MEF）。本研究旨在通过检测磷酸肌醇-3激酶（PI 3 K）-Akt-哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的功能作用，进一步探讨自噬在坏死中的调节作用。我们最初有趣的发现是，胰岛素能够促进在L929细胞中由zVAD和MNNG诱导的坏死性细胞死亡或在全生长培养基中培养的DKO MEF细胞中由H2 O2诱导的坏死性细胞死亡。胰岛素的促坏死功能进一步得到以下观察结果的支持：胰岛素能够消除饥饿对L929细胞中WAD诱导的坏死细胞死亡的保护作用。接下来，我们证明了胰岛素作用于PI 3 K-Akt-mTOR通路以促进坏死，因为通过化学抑制剂（LY 294002和雷帕霉素）或mTOR敲低抑制上述通路能够减轻胰岛素的促死亡功能。最后，我们提供的证据表明，胰岛素的促死亡功能依赖于其对自噬的抑制作用，自噬在坏死中起着重要的促存活功能。总之，在这里，我们提供了令人信服的证据，表明PI 3 K-Akt-mTOR信号通路的激活可以通过抑制自噬促进坏死细胞死亡，至少在我们的研究中定义的坏死模型中，自噬作为促生存功能。这项研究的数据不仅进一步强调了自噬在坏死细胞死亡中的促生存功能，而且还提供了一种新的见解，即通过调节自噬将PI 3 K-Akt-mTOR信号通路与细胞死亡联系起来的复杂联系。
Our previous work has shown that autophagy plays a pro-survival function in two necrotic cell death models: zVAD-treated L929 cells as well as H2O2-treated Bax(-/-)Bak(-/-) mouse embryonic fibroblasts (DKO MEF). This study aims to further explore the regulatory role of autophagy in necrosis by examining the functional role of the phosphoinositide-3 kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway. Our initial intriguing finding was that insulin is able to promote necrotic cell death induced by zVAD and MNNG in L929 cells or by H2O2 in DKO MEF cells cultured in full-growth medium. The pro-necrosis function of insulin was further supported by the observations that insulin is capable of abolishing the protective effect of starvation on necrotic cell death induced by WAD in L929 cells. Next, we demonstrated that insulin acts on the PI3K-Akt-mTOR pathway to promote necrosis as the suppression of the above pathway by either chemical inhibitors (LY294002 and rapamycin) or mTOR knockdown is able to mitigate the pro-death function of insulin. Finally, we provided evidence that the pro-death function of insulin is dependent on its inhibitory effect on autophagy, which serves as an important pro-survival function in necrosis. Taken together, here we provide compelling evidence to show that activation of the PI3K-Akt-mTOR signaling pathway can promote necrotic cell death via suppression of autophagy, at least in the necrosis models defined in our study in which autophagy serves as a pro-survival function. Data from this study not only further underscore the pro-survival function of autophagy in necrotic cell death, but also provide a novel insight into the intricate connections linking the PI3K-Akt-mTOR signaling pathway with cell death via modulation of autophagy.