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 chemoresistanceto 6 head and neck squamous cell carcinomacell lines carrying p53 mutations. Cell lines werechosen, based on the presence of EGFR amplifications,the presence of H-ras mutations, and theabsence of either. WST-1 viability assays showedthat, in response to etoposide, Ca922 was mostsensitive, HOC313 most resistant, and HSC6 andthe others moderately sensitive. A similar tendencywas shown by further analyses with cisplatin, 5-fluorouracil,LY294002, and combined treatment withLY294002 and TNF-related apoptosis-inducing ligand(TRAIL). Although both Ca922 and HOC313 hadactivating mutations upstream of Akt signaling, theconstitutive phosphorylation of Akt at S473 wasobserved in chemosensitive Ca922, but not inchemoresistant HOC313, suggesting that constitutiveAkt phosphorylation was not the primarydeterminant for chemoresistance in these celllines. Further, by the combined treatment withLY294002 and TRAIL, apoptosis was induced inCa922 and HSC6 but not in HOC313. Interestingly,caspase 8 was not detected in HOC313, while itwas cleaved in the other 2 cell lines. Further, inCa922 and HSC6 but not in HOC313, caspase 8inhibitor restored loss of viability induced eitherwith LY294002 and TRAIL or even with etoposidealone. These findings suggest that caspase 8played an important role in chemoresistanceagainst genotoxic drugs.