COX-2 is essential for EGF induction of cell proliferation in gastric RGM1 cells.
Growth factors upregulate cyclooxygenase-2 (COX-2) expression and extracellular signal-regulated kinase (ERK) activity, yet little is known regarding the interaction between COX-2 and ERK in terms of mitogenic signal transduction pathways in gastric epithelial cells. Therefore, we examined the role of COX-2 in EGF-induced proliferation of gastric epithelial RGM1 cells. EGF treatment significantly induced ERK activity (peaked at 30 min) and significantly increased COX-2 protein (peaked at 6 hr), production of prostaglandin E2 (PGE2), and cell proliferation. MEK inhibitor (PD98059) decreased ERK activity and cell proliferation induced by EGF. The selective COX-2 inhibitor (NS-398) significantly reduced EGF-induced cell proliferation. Exogenous PGE2 partly reversed the NS-398-induced inhibitory action on cell proliferation, clearly indicating the importance of PGE2 in mitogenic pathway. The induction of COX-2 protein by EGF was completely blocked by preincubation with MEK inhibitor. These results suggest that the ERK-COX-2 pathway is critical for EGF-induced proliferation of gastric epithelial cells.
Sasaki
Eiji
E
Department of Gastroenterology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
Tominaga
Kazunari
K
Watanabe
Toshio
T
Fujiwara
Yasuhiro
Y
Oshitani
Nobuhide
N
Matsumoto
Takayuki
T
Higuchi
Kazuhide
K
Tarnawski
A S
AS
Arakawa
Tetsuo
T
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013270:Stomach / Q000166:cytology*; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005419:Flavonoids; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one