ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Antioxid Redox Signal. 2011 Dec 15;15(12):2975-87. doi: 10.1089/ars.2010.3851. Epub 2011 Jul 12.
Mitochondria play a critical role as death amplifiers during drug-induced apoptosis in cancer cells by providing pro-apoptotic factors that are released from the mitochondrial inter-membranous space upon the induction of mitochondrial outer membrane permeabilization. This intrinsic death signaling pathway is the preferred mechanism employed by most anticancer compounds, and as such, resistance to drug-induced apoptosis is invariably associated with inhibition of mitochondrial death signaling network. The latter is a function of a balance between the pro- and the anti-apoptotic members of the Bcl-2 family. Bcl-2 is the prototype anti-apoptotic protein that localizes to the mitochondria and blocks the recruitment and activation of pro-apoptotic proteins, such as Bax, to the mitochondria.
Recent evidence has highlighted a novel mechanism of anti-apoptotic activity of Bcl-2 in addition to its canonical activity in regulating mitochondrial outer membrane permeabilization. This novel activity is a function of cellular redox regulation, in particular, mitochondrial metabolism in cancer cells.
Here we review the current state of our understanding of the death inhibitory activity of Bcl-2 and provide insight into the novel functional biology of this remarkable protein, which could have implications for designing innovative strategies to overcome the problem of drug resistance in the clinical settings.
在线粒体介导的细胞凋亡过程中，线粒体作为“死亡放大器”发挥着关键作用，为细胞凋亡提供了促凋亡因子，这些因子在诱导线粒体外膜通透性时从线粒体膜间腔释放出来。这种内在的死亡信号通路是大多数抗癌化合物所采用的首选机制，因此，对药物诱导的细胞凋亡的耐药性总是与线粒体死亡信号网络的抑制有关。后者是 Bcl-2 家族的促凋亡和抗凋亡成员之间平衡的功能。Bcl-2 是一种典型的抗凋亡蛋白，定位于线粒体，阻止 Bax 等促凋亡蛋白被招募到线粒体并被激活。
最近的证据强调了 Bcl-2 的抗凋亡活性的一种新机制，除了其在调节线粒体外膜通透性方面的经典活性之外。这种新的活性是细胞氧化还原调节的功能，特别是癌细胞中线粒体代谢的功能。
在这里，我们回顾了我们目前对 Bcl-2 抑制死亡活性的理解，并深入了解了这种非凡蛋白质的新功能生物学，这可能对设计克服临床环境中药物耐药性问题的创新策略具有重要意义。
