The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (c-Met), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time- and dose- dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.
Cell Line, Tumor ; Cell Proliferation/drug effects ; Culture Media, Serum-Free ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/pharmacology ; Hepatocyte Growth Factor/*pharmacology ; Humans ; Imidazoles/pharmacology ; Kinetics ; MAP Kinase Kinase 1/metabolism ; Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism ; Neoplasm Metastasis ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Research Support, Non-U.S. Gov't ; Stomach Neoplasms/*enzymology/*pathology ; Urinary Plasminogen Activator/*secretion ; p38 Mitogen-Activated Protein Kinases/metabolism