Role of caspase 8 as a determinant in chemosensitivity of p53-mutated head and neck squamous cell carcinoma cell lines

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  • Kaneda Yoshimasa
    Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University Oral and Maxillofacial Surgery, Tokyo Medical and Dental University
  • Shimamoto Hiroaki
    Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University Oral and Maxillofacial Surgery, Tokyo Medical and Dental University
  • Matsumura Kouji
    Laboratory of Cell Analysis, Central Research Institute, National Defense Medical College
  • Ramanathan Arvind
    Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University
  • Shengliang Zhang
    Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University
  • Sakai Eiki
    Department of Oral and Maxillofacial Surgery, Dokkyo University School of Medicine
  • Omura Ken
    Oral and Maxillofacial Surgery, Tokyo Medical and Dental University
  • Tsuchida Nobuo
    Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University

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Abstract

We studied factors that control chemoresistance to 6 head and neck squamous cell carcinoma cell lines carrying p53 mutations. Cell lines were chosen, based on the presence of EGFR amplifications, the presence of H-ras mutations, and the absence of either. WST-1 viability assays showed that, in response to etoposide, Ca922 was most sensitive, HOC313 most resistant, and HSC6 and the others moderately sensitive. A similar tendency was shown by further analyses with cisplatin, 5-fluorouracil, LY294002, and combined treatment with LY294002 and TNF-related apoptosis-inducing ligand (TRAIL). Although both Ca922 and HOC313 had activating mutations upstream of Akt signaling, the constitutive phosphorylation of Akt at S473 was observed in chemosensitive Ca922, but not in chemoresistant HOC313, suggesting that constitutive Akt phosphorylation was not the primary determinant for chemoresistance in these cell lines. Further, by the combined treatment with LY294002 and TRAIL, apoptosis was induced in Ca922 and HSC6 but not in HOC313. Interestingly, caspase 8 was not detected in HOC313, while it was cleaved in the other 2 cell lines. Further, in Ca922 and HSC6 but not in HOC313, caspase 8 inhibitor restored loss of viability induced either with LY294002 and TRAIL or even with etoposide alone. These findings suggest that caspase 8 played an important role in chemoresistance against genotoxic drugs.

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