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World J Gastroenterol ; 23(40): 7253-7264, 2017 Oct 28.
Article in English | MEDLINE | ID: mdl-29142472

ABSTRACT

AIM: To investigate the protective effect of prostaglandin E1 (PGE1) against endoplasmic reticulum (ER) stress-induced hepatocyte apoptosis, and to explore its underlying mechanisms. METHODS: Thapsigargin (TG) was used to induce ER stress in the human hepatic cell line L02 and hepatocarcinoma-derived cell line HepG2. To evaluate the effects of PGE1 on TG-induced apoptosis, PGE1 was used an hour prior to TG treatment. Activation of unfolded protein response signaling pathways were detected by western blotting and quantitative real-time RT-PCR. Apoptotic index and cell viability of L02 cells and HepG2 cells were determined with flow cytometry and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. RESULTS: Pretreatment with 1 µmol/L PGE1 protected against TG-induced apoptosis in both L02 cells and HepG2 cells. PGE1 enhanced the TG-induced expression of C/EBP homologous protein (CHOP), glucose-regulated protein (GRP) 78 and spliced X box-binding protein 1 at 6 h. However, it attenuated their expressions after 24 h. PGE1 alone induced protein and mRNA expressions of GRP78; PGE1 also induced protein expression of DNA damage-inducible gene 34 and inhibited the expressions of phospho-PKR-like ER kinase, phospho-eukaryotic initiation factor 2α and CHOP. Treatment with protein kinase A (PKA)-inhibitor H89 or KT5720 blocked PGE1-induced up-regulation of GRP78. Further, the cytoprotective effect of PGE1 on hepatocytes was not observed after blockade of GRP78 expression by H89 or small interfering RNA specifically targeted against human GRP78. CONCLUSION: Our study demonstrates that PGE1 protects against ER stress-induced hepatocyte apoptosis via PKA pathway-dependent induction of GRP78 expression.


Subject(s)
Alprostadil/pharmacology , Apoptosis/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Endoplasmic Reticulum Stress/drug effects , Heat-Shock Proteins/metabolism , Carbazoles/pharmacology , Cell Survival/drug effects , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Endoplasmic Reticulum Chaperone BiP , Eukaryotic Initiation Factor-2/metabolism , Heat-Shock Proteins/genetics , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/physiology , Humans , Isoquinolines/pharmacology , Phosphorylation , Pyrroles/pharmacology , RNA Interference , RNA, Small Interfering/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology , Thapsigargin/pharmacology , Transcription Factor CHOP/metabolism , Unfolded Protein Response/drug effects , X-Box Binding Protein 1/metabolism
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