PMID- 18794136
OWN - NLM
STAT- MEDLINE
DCOM- 20081014
LR  - 20211020
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 18
DP  - 2008 Sep 15
TI  - Coupling of endoplasmic reticulum stress to CDDO-Me-induced up-regulation of 
      death receptor 5 via a CHOP-dependent mechanism involving JNK activation.
PG  - 7484-92
LID - 10.1158/0008-5472.CAN-08-1318 [doi]
AB  - The synthetic triterpenoid methyl-2-cyano-3,12-dioxoolean-1,9-dien-28-oate 
      (CDDO-Me) is in phase I clinical trials as a novel cancer therapeutic agent. We 
      previously showed that CDDO-Me induces c-Jun NH(2)-terminal kinase 
      (JNK)-dependent death receptor 5 (DR5) expression and augments death 
      receptor-induced apoptosis. The current study focused on addressing how CDDO-Me 
      induces JNK-dependent DR5 expression. Analysis of DR5 promoter regions defines 
      that the CCAAT/enhancer binding protein homologous protein (CHOP) binding site is 
      responsible for CDDO-Me-induced transactivation of the DR5 gene. Consistently, 
      CDDO-Me induced DR5 expression and parallel CHOP up-regulation. Blockade of CHOP 
      up-regulation also abrogated CDDO-Me-induced DR5 expression. These results 
      indicate that CDDO-Me induces CHOP-dependent DR5 up-regulation. Moreover, the JNK 
      inhibitor SP600125 abrogated CHOP induction by CDDO-Me, suggesting a 
      JNK-dependent CHOP up-regulation by CDDO-Me as well. Importantly, knockdown of 
      CHOP attenuated CDDO-Me-induced apoptosis, showing that CHOP induction is 
      involved in CDDO-Me-induced apoptosis. Additionally, CDDO-Me increased the levels 
      of Bip, phosphorylated eukaryotic translation initiation factor 2alpha, inositol 
      requiring kinase 1alpha, and activating transcription factor 4, all of which are 
      featured changes during endoplasmic reticulum (ER) stress. Furthermore, 
      salubrinal, an inhibitor of ER stress-induced apoptosis, inhibited JNK activation 
      and up-regulation of CHOP and DR5 by CDDO-Me and protected cells from 
      CDDO-Me-induced apoptosis. Thus, ER stress seems to be important for 
      CDDO-Me-induced JNK activation, CHOP and DR5 up-regulation, and apoptosis. 
      Collectively, we conclude that CDDO-Me triggers ER stress, leading to 
      JNK-dependent, CHOP-mediated DR5 up-regulation and apoptosis.
FAU - Zou, Wei
AU  - Zou W
AD  - Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory 
      University School of Medicine, Atlanta, Georgia 30322, USA.
FAU - Yue, Ping
AU  - Yue P
FAU - Khuri, Fadlo R
AU  - Khuri FR
FAU - Sun, Shi-Yong
AU  - Sun SY
LA  - eng
GR  - P50 CA128613/CA/NCI NIH HHS/United States
GR  - P50 CA128613-020002/CA/NCI NIH HHS/United States
GR  - P50 CA128613-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DDIT3 protein, human)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 6SMK8R7TGJ (Oleanolic Acid)
RN  - CEG1Q6OGU1 (bardoxolone methyl)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/enzymology/metabolism/pathology
MH  - Endoplasmic Reticulum/*drug effects/metabolism
MH  - Enzyme Activation/drug effects
MH  - Glutathione/metabolism
MH  - Humans
MH  - Lung Neoplasms/drug therapy/enzymology/metabolism/pathology
MH  - MAP Kinase Kinase 4/*metabolism
MH  - Oleanolic Acid/*analogs & derivatives/pharmacology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*biosynthesis/genetics
MH  - Transcription Factor CHOP/*biosynthesis
MH  - Transcription, Genetic
MH  - Up-Regulation/drug effects
PMC - PMC2597446
MID - NIHMS60251
EDAT- 2008/09/17 09:00
MHDA- 2008/10/15 09:00
PMCR- 2009/09/15
CRDT- 2008/09/17 09:00
PHST- 2008/09/17 09:00 [pubmed]
PHST- 2008/10/15 09:00 [medline]
PHST- 2008/09/17 09:00 [entrez]
PHST- 2009/09/15 00:00 [pmc-release]
AID - 68/18/7484 [pii]
AID - 10.1158/0008-5472.CAN-08-1318 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Sep 15;68(18):7484-92. doi: 10.1158/0008-5472.CAN-08-1318.