Department of Clinical & Experimental Medicine, Division of Cell Biology, Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping, Sweden.
J Cell Mol Med. 2013 Jan;17(1):12-29. doi: 10.1111/jcmm.12001. Epub 2013 Jan 10.
The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer- and anti-ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia-induced damage. However, initial clinical studies on apoptosis-modulating drugs led to unexpected results in different clinical conditions and this may have been due to co-effects on non-apoptotic interconnected cell death mechanisms and the 'yin-yang' role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria (e.g. mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways (e.g. Bcl2-family members and p53). We also briefly highlight stress-induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation-induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.
20 世纪 90 年代，细胞凋亡调控方面的知识迅速积累，随后开发出了几种抗癌和抗缺血（中风或心肌梗死）的实验性药物。人们认为激活细胞凋亡途径或去除细胞凋亡抑制剂有助于癌症治疗，而抑制细胞凋亡则被认为可以限制缺血引起的损伤。然而，凋亡调节药物的初步临床研究在不同的临床情况下得出了意想不到的结果，这可能是由于它们对非凋亡性相互关联的细胞死亡机制以及自噬在生存与细胞死亡中的“阴阳”作用的共同影响。在这篇综述中，我们将细胞死亡的分析扩展到了细胞凋亡之外。在介绍了控制自噬和坏死（也称为坏死性凋亡或程序性坏死）的分子途径之后，我们专注于细胞死亡信号的相互关联特征，以及涉及线粒体的共同细胞死亡过程（例如自噬和线粒体凋亡）以及在多种途径中起主要作用的分子信号（例如 Bcl2 家族成员和 p53）。我们还简要介绍了应激诱导的细胞衰老，它不仅在机体衰老中起作用，而且为开发新的抗癌策略提供了可能。最后，我们在讨论辐射诱导的有丝分裂灾难时，简要说明了临床环境中细胞死亡形式的相互关联特征。我们讨论了这些信号通路与癌症生物学和治疗方法的关系。
