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Induction of Caspase 8 by Interferon Renders Some Neuroblastoma (NB) Cells Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) but Reveals That a Lack of Membrane TR1/TR2 Also Contributes to TRAIL Resistance in NB

Pediatric Oncology Branch [X. Y., M. S. M., C. L. M., C. J. T.] and Laboratory of Pathology [M. E. R., M. T.], National Cancer Institute, NIH, Bethesda, Maryland 20892; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, [L. H. W.]; and Children’s Hospital of the Albert-Ludwigs-University, 79106 Freiburg, Germany [U. K.]

The resistance of neuroblastoma (NB) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack of caspase 8 expression. Here we demonstrate a clinically applicable molecular targeting strategy that not only increases caspase 8 expression ex vivo in NB cell lines but also in the tumor tissues of NB patients receiving IFN- treatment. We identify the functional caspase 8 promoter, which is different from the methylated region reported previously, and show promoter activity is up-regulated by IFN- through a IFN- activation site-containing region. IFN- also induces TRAIL expression in NB cell lines. However, the IFN- restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in most NB cell lines examined. This additional lesion in the TRAIL path is because of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but in most of the NB tumor tissues evaluated. Restoration of TR2 expression by transfection enhances IFN--induced TRAIL sensitivity. Furthermore, we have found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8 with IFN- and TR2 with chemotherapeutic agents.

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