Disruption of apoptotic death signal transduction pathways may be responsible for
tumor formation, progression and resistance to treatment in
neuroblastoma.
Caspase 8, one of the
initiator caspases, plays an important role in the Fas-
Fas ligand pathway. This
caspase signals through the formation of a death-inducing signaling complex in response to Fas activation by its
ligand. In this study, we evaluated the sensitivity of a series of human
neuroblastoma cell lines to membrane-bound
Fas ligand induced-cell death, as well as the expression of Fas,
caspase 3 and
caspase 8. Sensitivity to Fas-mediated cell death did not correlate with the expression of Fas in
neuroblastoma cells, but was directly associated with the pattern of
caspase 8 protein expression. We found that the majority of
neuroblastoma cell lines we evaluated lacked
caspase 8 expression, and these cell lines were invariably resistant to Fas-mediated cell death. In contrast, cell lines expressing normal
caspase 8 protein were quite sensitive to Fas-mediated cell death. More interestingly, a group of cell lines expressing a distinct short form of
caspase 8 with splicing out of exon 3 consistently showed moderate sensitivity to Fas-mediated cell death. These results indicate that the profile of
caspase 8 expression is an important determinant of the response of
neuroblastoma cells to Fas-mediated cell death.