1.Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines.
Kyung Hee LEE ; Eun Young CHOI ; Min Kyoung KIM ; Myung Soo HYUN ; Byung Ik JANG ; Tae Nyeun KIM ; Sang Woon KIM ; Sun Kyo SONG ; Jung Hye KIM ; Jae Ryong KIM
Experimental & Molecular Medicine 2006;38(1):27-35
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
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Cell Proliferation/drug effects
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Culture Media, Serum-Free
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Dose-Response Relationship, Drug
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Enzyme Activation/drug effects
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Enzyme Inhibitors/pharmacology
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Extracellular Signal-Regulated MAP Kinases/metabolism
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Flavonoids/pharmacology
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Hepatocyte Growth Factor/*pharmacology
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Humans
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Imidazoles/pharmacology
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Kinetics
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MAP Kinase Kinase 1/metabolism
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Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
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Neoplasm Metastasis
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Phosphorylation/drug effects
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Pyridines/pharmacology
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Research Support, Non-U.S. Gov't
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Stomach Neoplasms/*enzymology/*pathology
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Urinary Plasminogen Activator/*secretion
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p38 Mitogen-Activated Protein Kinases/metabolism