The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells

摘要: Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved mediating extrinsic apoptotic pathway. Its role FTI-induced has not been reported. In this study, we investigated modulation DR5 by FTI lonafarnib and involvement up-regulation apoptosis. Lonafarnib activated caspase-8 its downstream caspases, whereas caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone small interfering RNA abrogated lonafarnib-induced apoptosis, indicating induces caspase-8-dependent up-regulated expression, increased cell-surface distribution, enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced Overexpression dominant-negative Fas-associated death domain mutant silencing expression using attenuated These results indicate critical DR5-mediated pathway By analyzing promoter, found induced CCAAT/enhancer-binding homologous (CHOP)-dependent transactivation promoter. CHOP expression. thus CHOP-dependent up-regulation. We conclude contributes to