Epigenetic Silencing of Caspase-8: A Novel Mechanism of Drug Resistance Which Can Be Overcome by Demethylating Agents, Histone Deacetylase Inhibitors, IFNy or Caspase-8 Gene Transfer

摘要

Resistance of many tumors to current treatment protocols still remains a major concern in cancer therapy and may be caused by defective apoptosis programs such as deficient expression of caspases. In cells resistant to treatment with TRAIL or anticancer drugs, caspase-8 protein and mRNA expression was decreased or absent without caspase-8 gene loss. IFNy sensitized resistant cells without caspase-8 by re-expression of caspase-8. Upregulation of caspase-8 and sensitization for apoptosis by IFNy was blocked by overexpression of dominant-negative mutants of Statl or in Statl-deficient U3 A cells, while complementation of Statl-deficient U3A cells with wild-type Statl restored the IFNy effect. These findings provide evidence that the Statl/IRFl pathway is involved in induction of caspase-8 expression and apoptosis initiated by IFNy and indicate that IFNy might be an effective strategy to sensitize various resistant tumor cells with deficient caspase-8 expression for chemotherapy- or death receptor-induced apoptosis.