Association of caspase-8 mutation with chemoresistance to cisplatin in HOC313 head and neck squamous cell carcinoma cells.
Caspase-8 is a critical upstream mediator of apoptosis in the death receptor pathway. However, the relationship between caspase-8 mutation and chemosensitivity remain unclear in head and neck squamous cell carcinoma (HNSCC) carrying p53 mutation. In this study, we identified a caspase-8 nonsense mutation, accompanied by the loss of the second allele, in a drug-resistant HOC313 HNSCC cell line. The nonsense mutation (R68X) leads to truncation of all defined functional domains. Reconstitution of caspase-8 by stable transfection of wild-type caspase-8 sensitized the cells to cisplatin-, but not etoposide-induced apoptosis. Consistent with this, cisplatin, but not etoposide, induced TNF-alpha and TRAIL mRNA in caspase-8 reconstituted HOC313 cells, accompanied by activation of the reconstituted caspase-8 and its downstream caspase-3. These results indicate that the loss of caspase-8 plays an important role in acquisition of chemoresistance to cisplatin in HOC313 cells.
Section of Molecular Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Juan
J
Liu
Hiroshi
H
Uematsu
Nobuo
N
Tsuchida
Masa-Aki
MA
Ikeda
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D053181:Caspase 8 / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018389:Codon, Nonsense; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000201:enzymology*; D006801:Humans; D053218:Receptors, Death Domain / Q000819:agonists / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D053218:Receptors, Death Domain; D016159:Tumor Suppressor Protein p53; D053181:Caspase 8; D002945:Cisplatin