Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis
Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis
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DOI：
10.1038/sj.onc.1204141
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发表时间：
2001-03-01
期刊：
影响因子：
8
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Fulda, S;Meyer, E;Debatin, KM
细胞凋亡的细胞应激反应，如治疗与细胞毒性药物是介导的效应半胱天冬酶（半胱天冬酶-3），可以激活不同的启动子途径，在这里，我们报告的细胞类型特异性触发死亡受体和/或线粒体途径后，药物治疗。在I型细胞（BJAB）中，受体和线粒体途径在药物处理后均被激活，因为通过显性负性FADD（FADD-DN）的过表达阻断受体途径或通过Bcl-X-L的过表达阻断线粒体途径仅部分抑制细胞凋亡，药物处理诱导形成的FADD-和caspase-8-含有CD 95死亡诱导信号复合物（DISC）在I型细胞中，导致caspase-8的激活，作为最顶端的caspase。相反，在II型细胞（Jurkat）中，凋亡主要由线粒体控制，因为Bcl-2的过表达完全阻断了药物诱导的凋亡，而FADD-DN的过表达没有保护作用。在这些细胞中，包括胱天蛋白酶-8的胱天蛋白酶被胱天蛋白酶驱动的信号传导事件激活，尽管CD 95、FADD和胱天蛋白酶-8蛋白的表达水平与I型细胞相当，但未检测到DISC。同样，药物诱导的CD 95聚集主要见于I型细胞。Bid在I型细胞中线粒体改变之前被裂解，提供了半胱天冬酶-8活化和线粒体扰动之间的分子联系，而在I型细胞中。TT细胞中，Bid在线粒体下游被切割，我们对细胞毒性药物的细胞类型特异性反应的发现对于鉴定不同肿瘤细胞中化学敏感性或抗性的分子参数具有意义。
Apoptosis in response to cellular stress such as treatment with cytotoxic drugs is mediated by effector caspases (caspase-3) which can be activated by different initiator pathways, Here, we report on a cell type specific triggering of death receptor and/or mitochondrial pathways upon drug treatment. In type I cells (BJAB), both the receptor and the mitochondrial pathway were activated upon drug treatment, since blockade of either the receptor pathway by overexpression of dominant negative FADD (FADD-DN) or of the mitochondrial pathway by overexpression of Bcl-X-L only partially inhibited apoptosis, Drug treatment induced formation of a FADD- and caspase-8-containing CD95 death-inducing signaling complex (DISC) in type I cells resulting in activation of caspase-8 as the most apical caspase. Tn contrast, in type II cells (Jurkat), apoptosis was predominantly controlled by mitochondria, since overexpression of Bcl-2 completely blocked drug-induced apoptosis, while overexpression of FADD-DN had no protective effect. In these cells, caspases including caspase-8 were activated by mitochondria-driven signaling events and no DISC was detected despite expression levels of CD95, FADD and caspase-8 proteins comparable to type I cells. Likewise, drug-induced CD95 aggregation was predominantly found in type I cells. Bid was cleaved prior to mitochondrial alterations in type I cells providing a molecular link between caspase-8 activation and mitochondrial perturbations, whereas in type. TT cells, Bid was cleaved downstream of mitochondria, Our findings of a cell type specific response to cytotoxic drugs have implications for the identification of molecular parameters for chemosensitivity or resistance in different tumor cells.