Caspase inhibitors promote alternative cell death pathways.
Caspase inhibitors promote alternative cell death pathways.
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DOI：
10.1126/stke.3582006pe44
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发表时间：
2006-10-24
期刊：
影响因子：
--
通讯作者：
Festjens, Nele
中科院分区：
文献类型：
--
作者：
Vandenabeele, Peter;Vanden Berghe, Tom;Festjens, Nele
半胱天冬酶抑制剂的使用揭示了存在用于细胞凋亡的替代备用细胞死亡程序。广谱半胱天冬酶抑制剂zVAD-favor调节三种主要类型的细胞死亡。添加zVAD-fatal阻断凋亡细胞死亡，使细胞对坏死细胞死亡敏感，并诱导自噬细胞死亡。几项研究表明，激酶RIP 1和腺苷核苷酸转运蛋白（ANT）-亲环素D（CypD）复合物在坏死性细胞死亡中起着至关重要的作用。zVAD介导的致敏坏死细胞死亡的潜在机制涉及抑制胱天蛋白酶-8介导的RIP 1蛋白水解和干扰ANT-CypD相互作用。RIP 1也参与自噬性细胞死亡。半胱天冬酶抑制剂和敲除研究揭示了过氧化氢酶和半胱天冬酶-8在自噬细胞死亡中的负面作用。RIP 1在坏死性和自噬性细胞死亡中的积极作用和caspase-8的消极作用表明，这两种类型的细胞死亡的途径是相互关联的。坏死性细胞死亡代表涉及线粒体活性氧（ROS）产生、三磷酸腺苷浓度降低和其他细胞损伤的快速细胞反应，而自噬性细胞死亡首先通过清理ROS损伤的线粒体作为存活尝试开始。然而，当这个过程过度发生时，自噬本身就会变得具有细胞毒性，最终导致自噬细胞死亡。更好地了解这些替代细胞死亡途径的分子机制，可以提供治疗工具，以打击与神经退行性疾病，缺血-再灌注病理学和感染性疾病相关的细胞死亡，也可以促进癌症治疗中替代细胞毒性策略的发展。
The use of caspase inhibitors has revealed the existence of alternative backup cell death programs for apoptosis. The broad-spectrum caspase inhibitor zVAD-fmk modulates the three major types of cell death. Addition of zVAD-fmk blocks apoptotic cell death, sensitizes cells to necrotic cell death, and induces autophagic cell death. Several studies have shown a crucial role for the kinase RIP1 and the adenosine nucleotide translocator (ANT)-cyclophilin D (CypD) complex in necrotic cell death. The underlying mechanism of zVAD-fmk-mediated sensitization to necrotic cell death involves the inhibition of caspase-8-mediated proteolysis of RIP1 and disturbance of the ANT-CypD interaction. RIP1 is also involved in autophagic cell death. Caspase inhibitors and knockdown studies have revealed negative roles for catalase and caspase-8 in autophagic cell death. The positive role of RIP1 and the negative role of caspase-8 in both necrotic and autophagic cell death suggest that the pathways of these two types of cell death are interconnected. Necrotic cell death represents a rapid cellular response involving mitochondrial reactive oxygen species (ROS) production, decreased adenosine triphosphate concentration, and other cellular insults, whereas autophagic cell death first starts as a survival attempt by cleaning up ROS-damaged mitochondria. However, when this process occurs in excess, autophagy itself becomes cytotoxic and eventually leads to autophagic cell death. A better understanding of the molecular mechanisms of these alternative cell death pathways may provide therapeutic tools to combat cell death associated with neurodegenerative diseases, ischemia-reperfusion pathologies, and infectious diseases, and may also facilitate the development of alternative cytotoxic strategies in cancer treatment.