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.
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 in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated lonafarnib-induced apoptosis, indicating that lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated lonafarnib-induced DR5 expression. These results thus indicate that lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to lonafarnib-induced apoptosis.
Sun
Shi-Yong
SY
Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA. shi-yong.sun@emoryhealthcare.org
Liu
Xiangguo
X
Zou
Wei
W
Yue
Ping
P
Marcus
Adam I
AI
Khuri
Fadlo R
FR
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D003986:Dibenzocycloheptenes
D053181:Caspase 8; D051231:Farnesyltranstransferase; D008565:Membrane Proteins; D010880:Piperidines; D011725:Pyridines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes