PMID- 24412748
OWN - NLM
STAT- MEDLINE
DCOM- 20140924
LR  - 20211203
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 26
IP  - 4
DP  - 2014 Apr
TI  - GW1929 inhibits alpha7 nAChR expression through PPARgamma-independent activation of p38 
      MAPK and inactivation of PI3-K/mTOR: The role of Egr-1.
PG  - 730-9
LID - S0898-6568(14)00007-2 [pii]
LID - 10.1016/j.cellsig.2013.12.019 [doi]
AB  - Studies demonstrated that peroxisome proliferator-activated receptor gamma 
      (PPARgamma) ligands reduce nicotine-induced non small cell lung carcinoma (NSCLC) 
      cell growth through inhibition of nicotinic acetylcholine receptor (nAChR) 
      mediated signaling pathways. However, the mechanisms by which PPARgamma ligands 
      inhibited nAChR expression remain elucidated. Here, we show that GW1929, a 
      synthetic PPARgamma ligand, not only inhibited but also antagonized the stimulatory 
      effect of acetylcholine on NSCLC cell proliferation. Interestingly, GW1929 
      inhibited alpha7 nAChR expression, which was not blocked by GW9662, an antagonist of 
      PPARgamma, or by PPARgamma siRNA, but was abrogated by the p38 MPAK inhibitor SB239063. 
      GW1929 reduced the promoter activity of alpha7 nAChR and induced early growth 
      response-1 (Egr-1) protein expression, which was overcame by SB239063, but 
      enhanced by inhibitors of PI3-K and mTOR. Silencing of Egr-1 blocked, while 
      overexpression of Egr-1 enhanced, the effect of GW1929 on alpha7 nAChR expression and 
      promoter activity. Finally, GW1929 induced Egr-1 bound to specific DNA areas in 
      the alpha7 nAChR gene promoter. Collectively, these results demonstrate that GW1929 
      not only inhibits but also antagonizes Ach-induced NSCLC cell growth by 
      inhibition of alpha7 nAChR expression through PPARgamma-independent signals that are 
      associated with activation of p38 MPAK and inactivation of PI3-K/mTOR, followed 
      by inducing Egr-1 protein and Egr-1 binding activity in the alpha7 nAChR gene 
      promoter. By downregulation of the alpha7 nAchR, GW1929 blocks cholinergic signaling 
      and inhibits NSCLC cell growth.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Hahn, Swei Sunny
AU  - Hahn SS
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies, University of 
      Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese 
      Medicine, Guangzhou, Guangdong Province 510006, China. Electronic address: 
      swhan2010@live.com.
FAU - Tang, Qing
AU  - Tang Q
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies, University of 
      Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese 
      Medicine, Guangzhou, Guangdong Province 510006, China.
FAU - Zheng, Fang
AU  - Zheng F
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies, University of 
      Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese 
      Medicine, Guangzhou, Guangdong Province 510006, China.
FAU - Zhao, Shunyu
AU  - Zhao S
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies, University of 
      Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese 
      Medicine, Guangzhou, Guangdong Province 510006, China.
FAU - Wu, Jingjing
AU  - Wu J
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies, University of 
      Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese 
      Medicine, Guangzhou, Guangdong Province 510006, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140108
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (2-chloro-5-nitrobenzanilide)
RN  - 0 (Anilides)
RN  - 0 (Benzophenones)
RN  - 0 (EGR1 protein, human)
RN  - 0 (Early Growth Response Protein 1)
RN  - 0 (PPAR gamma)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (alpha7 Nicotinic Acetylcholine Receptor)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - X8S066WKF4 (GW 1929)
SB  - IM
MH  - Anilides/pharmacology
MH  - Benzophenones/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Early Growth Response Protein 1/antagonists & inhibitors/genetics/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - PPAR gamma/antagonists & inhibitors/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Promoter Regions, Genetic
MH  - RNA Interference
MH  - RNA, Small Interfering/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Tyrosine/*analogs & derivatives/pharmacology
MH  - alpha7 Nicotinic Acetylcholine Receptor/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & 
      inhibitors/genetics/*metabolism
OTO - NOTNLM
OT  - Egr-1
OT  - GW1929
OT  - Human lung adenocarcinoma cells
OT  - PPARgamma
OT  - p38 MPAK
OT  - alpha7nAchR
EDAT- 2014/01/15 06:00
MHDA- 2014/09/25 06:00
CRDT- 2014/01/14 06:00
PHST- 2013/12/12 00:00 [received]
PHST- 2013/12/29 00:00 [accepted]
PHST- 2014/01/14 06:00 [entrez]
PHST- 2014/01/15 06:00 [pubmed]
PHST- 2014/09/25 06:00 [medline]
AID - S0898-6568(14)00007-2 [pii]
AID - 10.1016/j.cellsig.2013.12.019 [doi]
PST - ppublish
SO  - Cell Signal. 2014 Apr;26(4):730-9. doi: 10.1016/j.cellsig.2013.12.019. Epub 2014 
      Jan 8.