Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells.
Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells.
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DOI：
10.1016/j.cellsig.2011.12.025
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发表时间：
2012-05
影响因子：
4.8
通讯作者：
Wei-wei Zhang;Xiaopin Wang;Tongsheng Chen
中科院分区：
文献类型：
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作者：
Wei-wei Zhang;Xiaopin Wang;Tongsheng Chen
我们最近的研究表明，白藜芦醇（resveratrol，RV），一种在红葡萄皮以及其他食品中发现的天然植物多酚，通过内源性凋亡途径的下游因子，caspase-非依赖性AIF和较小程度的caspase-9，诱导人肺腺癌（ASTC-a-1）细胞凋亡。本研究旨在探讨内源性信号通路的上游介质巴克/Bax、Bim、Puma和Noxa在RV诱导人肺腺癌（ASTC-a-1和A549）细胞凋亡中的作用。RV处理显著诱导巴克而不是Bax的活化，并且通过shRNA沉默巴克而不是Bax几乎完全阻止了RV诱导的细胞死亡、线粒体功能障碍，并且还在很大程度上阻止了RV诱导的AIF释放，证明了在RV诱导的细胞凋亡期间巴克而不是Bax的优先参与。此外，尽管RV处理诱导了Mcl-1的显著降解，但通过shRNA敲低Mcl-1仅适度增加RV诱导的巴克活化。有趣的是，沉默Bim而不是Puma和Noxa显着减弱RV诱导的细胞死亡，线粒体膜电位的损失，和巴克激活，这表明Bim的重要作用。总的来说，我们的研究结果首次表明，RV诱导细胞凋亡主要是通过巴克，而不是Bak介导的AIF依赖性线粒体凋亡信号通路，其中Bim，而不是Puma和Noxa可能提供的力量，触发巴克激活和随后的凋亡在ASTC-a-1和A549细胞系。
Our recent study have shown that resveratrol (RV), a natural plant polyphenol found in red grape skins as well as other food product, induced apoptosis via the downstream factors, caspase-independent AIF and to lesser extent caspase-9, of intrinsic apoptosis pathway in human lung adenocarcinoma (ASTC-a-1) cells. This report is designed to explore the roles of the upstream mediators of the intrinsic pathway, such as Bak/Bax, Bim, Puma and Noxa, during RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1 and A549) cell lines. RV treatment remarkably induced the activation of Bak but not Bax, and silencing Bak but not Bax by shRNA almost completely prevented RV-induced cell death, mitochondrial dysfunction and also largely prevented RV-induced AIF release, demonstrating the preferential engagement of Bak but not Bax during RV-induced apoptosis. In addition, although RV treatment induced a significant degradation of Mcl-1, knockdown of Mcl-1 by shRNA only modestly increased RV-induced Bak activation. Interestingly, silencing Bim but not Puma and Noxa remarkably attenuated RV-induced cell death, loss of mitochondrial membrane potential, and Bak activation, suggesting the important roles of Bim. Collectively, our findings for the first time demonstrate that RV induces apoptosis dominantly via a Bak- but not Bax-mediated AIF-dependent mitochondrial apoptotic signaling pathway in which Bim but not Puma and Noxa may supply the force to trigger Bak activation and subsequent apoptosis in both ASTC-a-1 and A549 cell lines.