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.
