title: Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines.
abstract: 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.
authors.affiliation: Department of Hemato-Oncology, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Hyun
authors.forename: Byung Ik
authors.initials: BI
authors.lastname: Jang
authors.forename: Tae Nyeun
authors.initials: TN
authors.lastname: Kim
authors.forename: Sang Woon
authors.initials: SW
authors.lastname: Kim
authors.forename: Sun Kyo
authors.initials: SK
authors.lastname: Song
authors.forename: Jung Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D017228:Hepatocyte Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one