MOE Key Libratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
Cell Signal. 2012 May;24(5):1037-46. doi: 10.1016/j.cellsig.2011.12.025. Epub 2012 Jan 5.
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.
我们最近的研究表明，白藜芦醇（RV）是一种天然植物多酚，存在于红葡萄皮以及其他食品中，可通过内在凋亡途径的下游因子（无 caspase 的 AIF 和在较小程度上的 caspase-9）诱导人肺腺癌细胞（ASTC-a-1）凋亡。本报告旨在探讨内在途径的上游介质（如 Bak/Bax、Bim、Puma 和 Noxa）在 RV 诱导人肺腺癌细胞（ASTC-a-1 和 A549）系凋亡中的作用。RV 处理显著诱导 Bak 的激活，但不诱导 Bax 的激活，并且通过 shRNA 沉默 Bak 但不沉默 Bax几乎完全阻止了 RV 诱导的细胞死亡、线粒体功能障碍，并且也在很大程度上阻止了 RV 诱导的 AIF 释放，表明在 RV 诱导的凋亡中优先涉及 Bak 而不是 Bax。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 仅适度增加了 RV 诱导的 Bak 激活。有趣的是，沉默 Bim 但不沉默 Puma 和 Noxa 显著减弱了 RV 诱导的细胞死亡、线粒体膜电位丧失和 Bak 激活，表明 Bim 的重要作用。总之，我们的研究结果首次表明，RV 通过 Bak 而非 Bax 介导的 AIF 依赖性线粒体凋亡信号通路诱导凋亡，在该通路中，Bim 而不是 Puma 和 Noxa 可能提供触发 Bak 激活和随后凋亡的力，在 ASTC-a-1 和 A549 细胞系中均如此。
