Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression

TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apopto sis in adult malignant glioma and various other human solid tumor models bu t not in normal tissues. To characterize the TRAIL death pathway in childho od primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines we re tested for TRAIL-induced apoptosis, TRAIL-sensitivity of the PNET cell l ines was correlated with mRNA expression levels of TRAIL, its agonistic (TR AIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8, Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis, Sensit ivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP, However, all TRAIL-sensitive PNET cell lines expr essed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PN ET cell lines expressed caspase-8 protein. Treatment with the methyltransfe rase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting t hat gene methylation inhibits caspase-8 transcription in these cells. We co nclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resi stance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising ther apeutic approach for PNET that deserves further investigation.