PMID- 28358434
OWN - NLM
STAT- MEDLINE
DCOM- 20171102
LR  - 20171102
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Linking)
VI  - 15
IP  - 5
DP  - 2017 May
TI  - Effects of GSK2606414 on cell proliferation and endoplasmic reticulum 
      stress‑associated gene expression in retinal pigment epithelial cells.
PG  - 3105-3110
LID - 10.3892/mmr.2017.6418 [doi]
AB  - GSK2606414 is a novel, highly selective inhibitor of protein kinase R‑like 
      endoplasmic reticulum kinase (PERK). GSK2606414 and its analogues have recently 
      been demonstrated to delay tumor growth and prevent neurodegeneration. The 
      present study investigated the effects of GSK2606414 on proliferation, apoptosis, 
      and the expression of activating transcription factor 4 (ATF4), 
      CCAAT/enhancer‑binding protein homologous protein (CHOP) and vascular endothelial 
      growth factor (VEGF) in human retinal pigment epithelial (RPE) cells under 
      endoplasmic reticulum (ER) stress. ARPE‑19 human RPE cells were treated with 
      0.01‑50 microM GSK2606414, and ER stress was induced by thapsigargin (TG) treatment. 
      Cell proliferation was assessed using the Cell Counting kit‑8 cell viability 
      assay. Apoptosis was detected by Annexin‑V/propidium iodide double staining using 
      flow cytometry. Western blot analysis was used to measure eukaryotic initiation 
      factor 2alpha (eIF2alpha) phosphorylation levels. ATF4, CHOP and VEGF mRNA expression 
      levels were assessed using reverse transcription‑quantitative polymerase chain 
      reaction. GSK2606414 treatment inhibited RPE cell proliferation in a 
      dose‑dependent manner, however it did not induce apoptosis. In addition, 
      GSK2606414 treatment inhibited eIF2alpha phosphorylation and reduced CHOP and VEGF 
      mRNA expression levels in RPE cells under TG‑induced ER stress. To the best of 
      our knowledge, the present study is the first to demonstrate that GSK2606414 has 
      a potential antiproliferative effect in RPE cells in vitro. This effect appeared 
      to be achieved via inhibition of the PERK/ATF4/CHOP signaling pathway and 
      suppression of VEGF expression levels.
FAU - Jiang, Xintong
AU  - Jiang X
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Wei, Yantao
AU  - Wei Y
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Zhang, Ting
AU  - Zhang T
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Zhang, Zhaotian
AU  - Zhang Z
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Qiu, Suo
AU  - Qiu S
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Zhou, Xuezhi
AU  - Zhou X
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
FAU - Zhang, Shaochong
AU  - Zhang S
AD  - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen 
      University, Guangzhou, Guangdong 510060, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20170330
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 
      (7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine)
RN  - 0 (ATF4 protein, human)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (Indoles)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 67526-95-8 (Thapsigargin)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Activating Transcription Factor 4/genetics/metabolism
MH  - Adenine/*analogs & derivatives/pharmacology
MH  - Apoptosis/drug effects
MH  - CCAAT-Enhancer-Binding Proteins/drug effects
MH  - Cell Proliferation/drug effects
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Epithelial Cells/metabolism
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - Gene Expression/*drug effects
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Phosphorylation/drug effects
MH  - RNA, Messenger/metabolism
MH  - Retinal Pigment Epithelium/cytology/*drug effects/metabolism
MH  - Signal Transduction/drug effects
MH  - Thapsigargin/pharmacology
MH  - Transcription Factor CHOP/drug effects/genetics
MH  - Vascular Endothelial Growth Factor A/genetics
EDAT- 2017/03/31 06:00
MHDA- 2017/11/03 06:00
CRDT- 2017/03/31 06:00
PHST- 2016/01/13 00:00 [received]
PHST- 2017/01/17 00:00 [accepted]
PHST- 2017/03/31 06:00 [pubmed]
PHST- 2017/11/03 06:00 [medline]
PHST- 2017/03/31 06:00 [entrez]
AID - 10.3892/mmr.2017.6418 [doi]
PST - ppublish
SO  - Mol Med Rep. 2017 May;15(5):3105-3110. doi: 10.3892/mmr.2017.6418. Epub 2017 Mar 
      30.