The Role of BH3-Only Proteins in Tumor Cell Development, Signaling, and Treatment.
The Role of BH3-Only Proteins in Tumor Cell Development, Signaling, and Treatment.
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DOI：
10.1177/1947601911417177
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发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
Chipuk, Jerry E
中科院分区：
文献类型：
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作者：
Elkholi, Rana;Floros, Konstantinos V;Chipuk, Jerry E
肿瘤细胞已经设计了几种策略来阻断凋亡的线粒体途径，尽管内源性或药理学线索死亡。这种细胞死亡过程通过多种抗凋亡和促凋亡BCL-2家族蛋白的协调调节进行，这些蛋白最终影响线粒体外膜的完整性。一旦受损，线粒体释放促凋亡因子以促进半胱天冬酶活化和凋亡表型。在BCL-2家族内存在称为仅BH 3蛋白的促凋亡成员的亚类，其直接和/或间接地功能性调节剩余的抗凋亡和促凋亡BCL-2蛋白以损害线粒体并参与凋亡。这篇综述的重点是讨论BH 3-only蛋白的细胞和药理学调节，以更好地了解调节这类蛋白的信号通路和试剂。由于BH 3-only蛋白增加了细胞对促凋亡剂如化疗剂的敏感性，因此已经开发了许多小分子BH 3模拟物，并且目前处于临床试验的各个阶段。在综述的最后，将讨论小分子BH 3模拟物的发现和应用。
Tumor cells have devised several strategies to block the mitochondrial pathway of apoptosis despite endogenous or pharmacological cues to die. This process of cell death proceeds through the coordinated regulation of multiple anti-apoptotic and pro-apoptotic BCL-2 family proteins that ultimately impinge on the integrity of the outer mitochondrial membrane. Once compromised, mitochondria release pro-apoptotic factors to promote caspase activation and the apoptotic phenotype. Within the BCL-2 family exists a subclass of pro-apoptotic members termed the BH3-only proteins, which directly and/or indirectly functionally regulate the remaining anti- and pro-apoptotic BCL-2 proteins to compromise mitochondria and engage apoptosis. The focus of this review is to discuss the cellular and pharmacological regulation of the BH3-only proteins to gain a better understanding of the signaling pathways and agents that regulate this class of proteins. As the BH3-only proteins increase cellular sensitivity to pro-apoptotic agents such as chemotherapeutics, numerous small-molecule BH3 mimetics have been developed and are currently in various phases of clinical trials. Toward the end of the review, the discovery and application of the small-molecule BH3 mimetics will be discussed.