Loss of Caspase-8 Expression in Highly Malignant Human Neuroblastoma Cells Correlates with Resistance to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis
2000
Human neuroblastoma (NB) is a highly heterogeneous childhood cancer that
is aggressively malignant or can undergo spontaneous regression that
may involve apoptosis. NB-derived cell lines were tested for their
sensitivity to apoptosis induced by the tumor-selective ligand tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL). Noninvasive
S-type cell lines (NB cell lines of substrate adherent phenotype) are
highly sensitive to TRAIL, whereas invasive N-type cell lines (NB cell
lines of neuronal phenotype) are resistant. Whereas both S- and N-type
cell lines express TRAIL-R2, FADD, and caspase-3 and -10, only S-type
cells express caspase-8. Reduced levels of caspase-8 protein were also
observed in a malignant stage IV NB tumor when compared with a benign
ganglioneuroma. The caspase - 8 gene
is not deleted in either N-type NB cell lines or high-stage NB
tumors. Caspase-8 expression can be induced by demethylation with
5-aza-2′deoxycytidine, which enhances sensitivity to TRAIL. Therefore,
caspase-8 expression is silenced in malignant NB, which correlates to
tumor severity and resistance to TRAIL-induced apoptosis.
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