Role of caspase 8 as a determinant in chemosensitivity of p53-mutated head and neck squamous cell carcinoma cell lines.
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.
Kaneda
Yoshimasa
Y
Department of Molecular Cellular Oncology and Microbiology, Tokyo Medical and Dental University, Japan.
Shimamoto
Hiroaki
H
Matsumura
Kouji
K
Arvind
Ramanathan
R
Zhang
Shengliang
S
Sakai
Eiki
E
Omura
Ken
K
Tsuchida
Nobuo
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics; D053181:Caspase 8; D020169:Caspases / Q000502:physiology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002867:Chromones; D008562:Membrane Glycoproteins; D009025:Morpholines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D002945:Cisplatin; D005472:Fluorouracil