Rebamipide inhibits gastric cancer cell growth.
Rebamipide is an antiulcer drug used in Japan, Korea, China, Philippines, and other Asian countries for treatment of gastritis and peptic ulcer. Its effect on gastric cancer cell growth and its regulatory mechanisms remain unknown. We examined whether rebamipide affects human gastric cancer cell proliferation and activation of Smad signaling pathway. Gastric cancer (AGS) cells were treated with either (a) medium (control), (b) medium-containing rebamipide (0.5-2 mg/mL), or (c) PD98059+rebamipide. We determined cell proliferation, expression of p21, phosphorylation of ERK2, JNK p38, and Smad2/3, formation of Smad2/3-Smad4 complex, and nuclear translocation of Smad2/3. Rebamipide treatment inhibited AGS cell proliferation and increased p21, Smad2/3 phosphorylation, and Smad2/3-Smad4 complex formation. Rebamipide induced phosphorylation of ERK2 but not JNK or p38. Inactivation of ERK2 by PD98059 partly attenuated rebamipide-induced p21 expression. These data demonstrate that rebamipide activates Smad signaling pathway and suppresses human gastric cancer cell growth. Inactivation of ERK2 partly inhibited rebamipide-induced p21 expression, indicating a crosstalk between ERK and Smad signaling pathways.
Tanigawa
Tetsuya
T
Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
Pai
Rama
R
Arakawa
Tetsuo
T
Tarnawski
Andrzej S
AS
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010766:Phosphorylation; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000897:Anti-Ulcer Agents; D015363:Quinolones; D051785:Smad Proteins; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C052785:rebamipide; D000409:Alanine