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In neuroblastoma (NB) cells there are multiple defects in the death receptor pathway including decreased caspase 8 and TRAIL receptor (TR) expression. The caspase 8 deficiency correlates with N-myc amplification. We find that increased N-myc expression does not down-regulate caspase 8 mRNA expression or regulate the caspse 8 promoter. However, in a subgroup of NB cell lines that have an intact death receptor path, N-myc expression increases their sensitivity to TRAIL induced apoptosis. This may occur because there is a significant inverse correlation between N-myc amplification and expression of the IAP, c-FLIP. We tested 16 NB cell lines and found that 9/13 N-myc amplified NB cell lines have a very low level of c-FLIP expression, while all non-N-myc amplified cell lines have high c-FLIP expression. This would indicate that restoration of the TRAIL path in N-myc amplified cells would be a particularly efficacious therapeutic approach. Interferon-∂ (IFN-∂) treatment induces caspase 8 in neuroblastoma regardless of caspase 8 methylation status, and IFN-∂ does not change the methylation status of caspase 8. IFN-∂ also induces TRAIL expression in NB cells and leads to cell death in TR2 transfected NB. In primary cultures of neuroblastoma, INF∂ and NGF together are much more potent inducers of differentiation than either one used alone. Although another neurotrophin, BDNF, is known to make neuroblastoma cells more resistant to chemotherapy, we have found that activation of the TRAIL receptor path induces cell death even in NB cells with an active BDNF/TrkB path. So IFN-∂ may be an important therapeutic tool in the treatment of neuroblastoma because of its ability to complement defects in the TRAIL path, synergize with differentiation agents and overcome BDNF/TrkB chemoresistance.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]