PMID- 17493934
OWN - NLM
STAT- MEDLINE
DCOM- 20070913
LR  - 20220409
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 26
DP  - 2007 Jun 29
TI  - 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.
PG  - 18800-9
AB  - 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.
FAU - Sun, Shi-Yong
AU  - Sun SY
AD  - Department of Hematology and Oncology, Winship Cancer Institute, Emory University 
      School of Medicine, Atlanta, Georgia 30322, USA. shi-yong.sun@emoryhealthcare.org
FAU - Liu, Xiangguo
AU  - Liu X
FAU - Zou, Wei
AU  - Zou W
FAU - Yue, Ping
AU  - Yue P
FAU - Marcus, Adam I
AU  - Marcus AI
FAU - Khuri, Fadlo R
AU  - Khuri FR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20070509
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Membrane Proteins)
RN  - 0 (Piperidines)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.5.1.29 (Farnesyltranstransferase)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (Caspase 8)
RN  - IOW153004F (lonafarnib)
SB  - IM
MH  - Apoptosis/*drug effects/physiology
MH  - Caspase 8/metabolism
MH  - Cell Line, Tumor
MH  - Farnesyltranstransferase/*antagonists & inhibitors
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Lung Neoplasms/*pathology
MH  - Membrane Proteins/genetics
MH  - Piperidines/*pharmacology
MH  - Pyridines/*pharmacology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*genetics
MH  - Recombinant Proteins/pharmacology
MH  - TNF-Related Apoptosis-Inducing Ligand/pharmacology
MH  - Transcription Factor CHOP/*metabolism
MH  - Up-Regulation/drug effects
EDAT- 2007/05/12 09:00
MHDA- 2007/09/14 09:00
CRDT- 2007/05/12 09:00
PHST- 2007/05/12 09:00 [pubmed]
PHST- 2007/09/14 09:00 [medline]
PHST- 2007/05/12 09:00 [entrez]
AID - S0021-9258(20)87347-5 [pii]
AID - 10.1074/jbc.M611438200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Jun 29;282(26):18800-9. doi: 10.1074/jbc.M611438200. Epub 2007 
      May 9.