Interferon-γ Induces Caspase-8 in Neuroblastomas Without Affecting Methylation of Caspase-8 Promoter

Background: The expression of caspase-8, a cysteine protease that is crucial for the apoptotic cascade, is absent in a high percentage of neuroblastomas, the most frequent extracranial solid tumor of infants and children. Resistance of neuroblastomas to death-receptor (eg, tumor necrosis factor alpha (TNF-α) receptor)-mediated apoptosis is thought to be caused by loss of caspase-8 expression. Gene silencing by hypermethylation of caspase-8 promoter has been proposed for the loss of caspase-8 expression in neuroblastoma cells. Methods: To further evaluate the role of caspase-8 in neuroblastoma, we assessed the induction of caspase-8 expression in neuroblastoma cells by treating the cells with a physiologic agent such as interferon-γ. Results: The authors found that interferon-γ induces caspase-8 expression in neuroblastoma cells irrespective of the gene silenced by hypermethylation of caspase-8 promoter. The authors show that interferon-γ also regulates other apoptosis related gene expression. Moreover, they show that interferon-γ treatment in combination with TNF-α decreases neuroblastoma cell proliferation. Conclusions: Interferon-γ induces procaspase-8 expression in neuroblastoma cells, and this induction is not dependent on demethylation of the caspase-8 promoter. Therapies aimed at inducing caspase-8 expression by adjunctive treatment, such as interferon-γ, may increase the effectiveness of current chemotherapeutic regimens.