IFNγ sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway

作者: Simone Fulda , Klaus-Michael Debatin

DOI: 10.1038/SJ.ONC.1205255

关键词:

摘要: Resistance of tumors to cytotoxic therapy may be due disrupted apoptosis programs and remains a major obstacle in cancer treatment. Here, we report that IFNγ sensitizes resistant tumor cells with absent or low caspase-8 expression for induced by death-inducing ligands drugs upregulating through Stat1/IRF1 dependent pathway. Combined treatment using TRAIL, APO1, TNFα cooperated trigger various cell lines derived from Ewing tumor, neuroblastoma medulloblastoma, while single agents exerted only minimal effect. Importantly, also inactivation the gene hypermethylation, although no direct effect on methylation status regulatory sequences was found. IFNγ-mediated facilitation inhibited specific inhibitor zIETD.fmk mutant Jurkat implying prominent role mediating sensitization IFNγ. Upregulation blocked overexpression dominant-negative mutants Stat1 Stat1-deficient U3A cells, complementation wild-type restored Moreover, ectopic IRF1 thereby sensitizing TRAIL-, APO1- doxorubicin-induced apoptosis. These findings provide evidence pathway is involved induction initiated indicate might an effective strategy sensitize deficient chemotherapy- death receptor-induced

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