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.
Liu
Juan
J
Section of Molecular Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Uematsu
Hiroshi
H
Tsuchida
Nobuo
N
Ikeda
Masa-Aki
MA
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