Hepatocyte growth factor protects gastric epithelial cells against ceramide-induced apoptosis through induction of cyclooxygenase-2.
Forced overexpression of cyclooxygenase-2 (COX-2) in intestinal cells has been shown to be associated with resistance to apoptosis. However, the role of physiologically-induced COX-2 in the regulation of apoptosis remains unclear. In the present study, we examined whether hepatocyte growth factor (HGF)-induced COX-2 affects ceramide-induced apoptosis in RGM-1 gastric epithelial cells. An externally applied cell permeable ceramide analogue, C2-ceramide, caused RGM-1 cell death in a dose-dependent manner, whereas an inactive ceramide analogue, C2-dihydroceramide, did not. TdT-mediated dUTP nick end labeling (TUNEL) assay showed that the C2-ceramide-induced cell death was apoptosis. Application of HGF rapidly induced the expression of COX-2, and HGF prevented the apoptotic cell death induced by C2-ceramide. However, the anti-apoptotic action of HGF was antagonized by coapplication of NS-398, a selective inhibitor of COX-2. Thus, these results indicate that COX-2 is involved in the survival signaling from HGF in gastric epithelial cells, and suggest a role for physiologically-induced COX-2 in the protection of the cells from apoptosis.
Shimada
T
T
Department of Gastroenterology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. tshimada@dokkyomed.ac.jp
Hiraishi
H
H
Terano
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic
D002518:Ceramides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; C064769:N-acetylsphingosine; D009578:Nitrobenzenes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013449:Sulfonamides; C109343:dihydroceramide; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013110:Sphingosine