Taxol induces caspase-10-dependent apoptosis
Taxol induces caspase-10-dependent apoptosis
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DOI：
10.1074/jbc.m406543200
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发表时间：
2004-12-03
影响因子：
4.8
通讯作者：
Safa, AR
中科院分区：
文献类型：
--
作者：
Park, SJ;Wu, CH;Safa, AR
已知紫杉醇（紫杉醇）抑制细胞生长并在各种癌细胞中引发显著的凋亡。虽然紫杉醇诱导癌细胞凋亡，但其确切的作用机制尚不清楚。在这项研究中，我们研究了死亡受体，Fas相关的死亡结构域蛋白（FADD），半胱天冬酶-10和-8以及下游半胱天冬酶的激活，活性氧（ROS）在紫杉醇诱导的CCRF-HSB-2人淋巴细胞白血病细胞系凋亡。用Fas、肿瘤坏死因子（TNF）-α受体1或TNF相关凋亡诱导配体受体（DR 4和DR 5）的中和抗体预处理细胞不影响紫杉醇诱导的凋亡，但用显性阴性FADD质粒转染细胞导致紫杉醇诱导的凋亡抑制，表明紫杉醇诱导的凋亡独立于这些死亡受体，但依赖于FADD。此外，药物诱导半胱天冬酶-10、-8、-6和-3的活化，切割Bcl-2、Bid、聚（ADP-核糖）聚合酶和核纤层蛋白B，并下调FLICE样抑制蛋白（FLIP）和X染色体连锁凋亡抑制蛋白（XIAP）的细胞水平。然而，尽管细胞色素c从紫杉醇处理的细胞中的线粒体释放，caspase-9没有被激活。半胱天冬酶-8，-6，或-3抑制剂部分抑制紫杉醇诱导的细胞凋亡，而半胱天冬酶-10抑制剂完全废除这一进程。紫杉醇诱导的细胞凋亡也与线粒体膜电位（DeltaPsim）降低和ROS生成显著增加有关。然而，增加的ROS产生并不直接参与紫杉醇引发的细胞凋亡。因此，这些结果首次表明，紫杉醇诱导FADD依赖性细胞凋亡主要通过激活caspase-10，但独立于死亡受体。
Taxol ( paclitaxel) is known to inhibit cell growth and trigger significant apoptosis in various cancer cells. Although taxol induces apoptosis of cancer cells, its exact mechanism of action is not yet known. In this study we investigated death receptors, FAS-associated death domain protein (FADD), the activation of caspases-10 and - 8 as well as the downstream caspases, and reactive oxygen species (ROS) in taxol-induced apoptosis in the CCRF-HSB-2 human lymphoblastic leukemia cell line. Pretreating the cells with neutralizing antibodies to Fas, tumor necrosis factor (TNF)-alpha receptor 1, or TNF-related apoptosis-inducing ligand receptors (DR4 and DR5) did not affect taxol-induced apoptosis, but transfection of the cells with a dominant negative FADD plasmid resulted in inhibition of taxol-induced apoptosis, revealing that taxol induces apoptosis independently of these death receptors but dependently on FADD. Furthermore, the drug induced activation of caspases-10, - 8, - 6, and - 3, cleaved Bcl-2, Bid, poly(ADP-ribose) polymerase, and lamin B, and down-regulated cellular levels of FLICE-like inhibitory protein ( FLIP) and X-chromosome-linked inhibitor of apoptosis protein ( XIAP). However, despite the release of cytochrome c from the mitochondria in taxol-treated cells, caspase-9 was not activated. Inhibitors of caspases-8, - 6, or - 3 partially inhibited taxol-induced apoptosis, whereas the caspase-10 inhibitor totally abrogated this process. Taxol-induced apoptosis was also associated with decreased mitochondrial membrane potential (DeltaPsim) and a significant increase in ROS generation. However, increased ROS production was not directly involved in taxol-triggered apoptosis. Therefore, these results demonstrate for the first time that taxol induces FADD-dependent apoptosis primarily through activation of caspase-10 but independently of death receptors.