title: Involvement of NF-kappaB and mitochondrial pathways in docetaxel-induced apoptosis of human oral squamous cell carcinoma.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Shinohara
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sato
authors.forename: Seishi
authors.initials: S
authors.lastname: Echigo
authors.forename: Hidemi
authors.initials: H
authors.lastname: Rikiishi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D000077143:Docetaxel; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D043823:Taxoids; D000077143:Docetaxel; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases