ROS, Apoptosis and Cancer Biology Laboratory, Department of Physiology, Yong Loo Lin School of Medicine Singapore, Singapore ; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore Singapore, Singapore.
Front Oncol. 2013 Jan 2;2:206. doi: 10.3389/fonc.2012.00206. eCollection 2012.
Cell fate regulation is a function of diverse cell signaling pathways that promote cell survival and or inhibit cell death execution. In this regard, the role of the Bcl-2 family in maintaining a tight balance between cell death and cell proliferation has been extensively studied. The conventional dogma links cell fate regulation by the Bcl-2 family to its effect on mitochondrial permeabilization and apoptosis amplification. However, recent evidence provide a novel mechanism for death regulation by the Bcl-2 family via modulating cellular redox metabolism. For example overexpression of Bcl-2 has been shown to contribute to a pro-oxidant intracellular milieu and down-regulation of cellular superoxide levels enhanced death sensitivity of Bcl-2 overexpressing cells. Interestingly, gene knockdown of the small GTPase Rac1 or pharmacological inhibition of its activity also reverted death phenotype in Bcl-2 expressing cells. This appears to be a function of an interaction between Bcl-2 and Rac1. Similar functional associations have been described between the Bcl-2 family and other members of the Ras superfamily. These interactions at the mitochondria provide novel opportunities for strategic therapeutic targeting of drug-resistant cancers.
细胞命运的调节是多种细胞信号通路的功能，这些信号通路促进细胞存活和/或抑制细胞死亡执行。在这方面，Bcl-2 家族在维持细胞死亡和增殖之间的紧密平衡方面的作用已经得到了广泛的研究。传统观点将 Bcl-2 家族通过调节线粒体通透性和凋亡放大来调节细胞命运与凋亡联系起来。然而，最近的证据提供了一种通过调节细胞氧化还原代谢来调节死亡的新机制。例如，Bcl-2 的过表达已被证明有助于产生促氧化的细胞内环境，而细胞内超氧水平的下调增强了 Bcl-2 过表达细胞的死亡敏感性。有趣的是，小 GTPase Rac1 的基因敲低或其活性的药理学抑制也使 Bcl-2 表达细胞的死亡表型恢复正常。这似乎是 Bcl-2 与 Rac1 之间相互作用的一种功能。Bcl-2 家族和 Ras 超家族的其他成员之间也描述了类似的功能关联。这些在线粒体的相互作用为耐药性癌症的战略治疗靶向提供了新的机会。
