Cregan Sean P, Dawson Valina L, Slack Ruth S
Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Rd., Ottawa, Canada K1H 8M5.
Oncogene. 2004 Apr 12;23(16):2785-96. doi: 10.1038/sj.onc.1207517.
The major challenge in treating cancer is that many tumor cells carry mutations in key apoptotic genes such as p53, Bcl family proteins or those affecting caspase signaling. Such defects render treatment with traditional chemotherapeutic agents ineffective. Many studies have demonstrated the importance of caspase-independent cell death pathways in injury, degenerative diseases and tumor tissue. It is now recognized that in addition to their critical role in the production of cellular energy, mitochondria are also the source of key proapoptotic molecules involved in caspase activation. More recently, it has been discovered that in response to apoptotic stimuli, mitochondria can also release caspase-independent cell death effectors such as AIF and Endonuclease G. In this review, we examine the role of Bcl family proteins and poly(ADP-ribose) polymerase-1 signaling in the regulation of these apoptotic pathways and address the ongoing controversies in this field. Continued study of the mechanisms of apoptosis including caspase-independent death processes are likely to reveal novel therapeutic targets for the treatment of diverse human pathologies including cancer, neurodegenerative diseases and acute injuries such as stroke or myocardial infarction.
治疗癌症的主要挑战在于，许多肿瘤细胞在关键凋亡基因（如p53、Bcl家族蛋白或影响半胱天冬酶信号传导的基因）中携带突变。这些缺陷使得传统化疗药物治疗无效。许多研究已经证明了不依赖半胱天冬酶的细胞死亡途径在损伤、退行性疾病和肿瘤组织中的重要性。现在人们认识到，线粒体除了在细胞能量产生中起关键作用外，也是参与半胱天冬酶激活的关键促凋亡分子的来源。最近，人们发现，在对凋亡刺激作出反应时，线粒体还可以释放不依赖半胱天冬酶的细胞死亡效应分子，如凋亡诱导因子（AIF）和核酸内切酶G。在这篇综述中，我们研究了Bcl家族蛋白和聚（ADP-核糖）聚合酶-1信号传导在这些凋亡途径调节中的作用，并探讨了该领域中持续存在的争议。对凋亡机制（包括不依赖半胱天冬酶死亡过程）的持续研究，可能会揭示出针对包括癌症、神经退行性疾病以及中风或心肌梗死等急性损伤在内的多种人类疾病的新型治疗靶点。
