Loss of caspase-8 expression in highly malignant human neuroblastoma cellscorrelates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis

Human neuroblastoma (NB) is a highly heterogeneous childhood cancer that is aggressively malignant or can undergo spontaneous regression that may invo lve apoptosis, NB-derived cell Lines were tested for their sensitivity to a poptosis induced by the tumor-selective ligand tumor necrosis factor-relate d apoptosis-inducing ligand (TRAIL). Noninvasive S-type cell lines (NB cell lines of substrate adherent phenotype) are highly sensitive to TRAIL, wher eas invasive N-type cell lines (NB cell lines of neuronal phenotype) are re sistant. 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 c aspase-8 protein were also observed in a malignant stage IV NB tumor when c ompared 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 c an be induced by demethylation with 5-aza-2'deoxycytidine, which enhances s ensitivity to TRAIL. Therefore, caspase-8 expression is silenced in maligna nt NB, which correlates to tumor severity and resistance to TRAIL-induced a poptosis.