Involvement of NF-κB and mitochondrial pathways in docetaxel-induced apoptosis of human oral squamous cell carcinoma
Involvement of NF-κB and mitochondrial pathways in docetaxel-induced apoptosis of human oral squamous cell carcinoma
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DOI：
10.3892/ijmm.15.4.667
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发表时间：
2005-04
影响因子：
5.4
通讯作者：
T. Taniguchi;Masato Takahashi;F. Shinohara;Tomonori Sato;S. Echigo;H. Rikiishi
中科院分区：
文献类型：
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作者：
T. Taniguchi;Masato Takahashi;F. Shinohara;Tomonori Sato;S. Echigo;H. Rikiishi
多西他赛诱导的细胞凋亡干扰微管聚合动力学，临床上用于治疗晚期癌症，但在鳞状细胞癌中尚未完全确定。在这项研究中，研究了多西他赛治疗中涉及的细胞凋亡事件。当人口腔鳞状细胞癌细胞系HSC-3暴露于多西他赛72 h时，使用TUNEL法观察到凋亡的剂量依赖性效应。我们观察到半胱天冬酶级联的激活，包括半胱天冬酶-3、-8和-9等活性。泛半胱天冬酶抑制剂z-VAD-favor阻止了多西他赛（0.1 μ M）诱导的细胞凋亡，表明半胱天冬酶参与了这一过程。由于拮抗性CD 95-抗体（ZB 4）对紫杉醇诱导的细胞凋亡没有影响，因此CD 95/CD 95 L相互作用不参与该途径。caspase-8样活性不仅被IETD-fastin（caspase-8）抑制，而且被DEVD-fastin（caspase-3）抑制。结果表明，caspase-8样激活发生在DEVDase下游。多西紫杉醇促进线粒体中活性氧（ROS）的形成，并与抗氧化剂（如N-乙酰半胱氨酸和吡咯烷二硫代氨基甲酸酯）预孵育细胞，防止多西紫杉醇介导的细胞凋亡。此外，多西他赛治疗引起线粒体膜电位降低，细胞色素c释放到胞质溶胶，治疗48小时后。我们观察到多西他赛治疗后NF-κ B共有位点的结合活性和通过NF-κ B干扰线粒体功能。阻止NF-κ B的促凋亡特性抑制紫杉醇诱导的细胞凋亡。因此，这些结果表明，在多西他赛激活NF-κ B后，凋亡是通过依赖于紫杉醇的途径引起的。
Apoptosis induced by docetaxel that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers, has not been fully defined in squamous cell carcinoma. In this study, apoptotic events involved in docetaxel treatment were investigated. When the human oral squamous cell carcinoma cell line HSC-3 was exposed to docetaxel for 72 h, a dose-dependent effect was observed in apoptosis using the TUNEL method. We observed activation of caspase cascade including activities like caspase-3, -8, and -9. And the pan-caspase inhibitor z-VAD-fmk prevented apoptosis induced by docetaxel (0.1 microM), showing participation of caspases in this process. Since an antagonistic CD95-antibody (ZB4) exerted no effect on docetaxel-induced apoptosis, CD95/CD95L interaction was not involved in this pathway. The caspase-8-like activity was inhibited not only by IETD-fmk (caspase-8) but also by DEVD-fmk (caspase-3). The results indicate that the caspase-8-like activation occurred downstream of DEVDase. Docetaxel promoted the formation of reactive oxygen species (ROS) in mitochondria, and preincubation of cells with anti-oxidants such as N-acetyl cysteine and pyrrolidine dithiocarbamate, protected against apoptosis mediated by docetaxel. Furthermore, treatment with docetaxel elicited reduction of mitochondrial membrane potential, and release of cytochrome c to cytosol, after 48 h of treatment. We observed binding activity to NF-kappaB consensus site and interference with the mitochondrial function via NF-kappaB after docetaxel treatment. Preventing pro-apoptotic property of NF-kappaB inhibited docetaxel-induced apoptosis. Thus, these results suggest that, following the activation of NF-kappaB by docetaxel, apoptosis is elicited through a mitochondria-dependent pathway.