Exp Mol Med.  2006 Feb;38(1):27-35.

Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines

Affiliations
  • 1Department of Hemato-Oncology, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
  • 2Department of Gastroenterology, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
  • 3Department of General Surgery, College of Medicine, Yeungnam University, Daegu 705-717, Korea.
  • 4Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-717, Korea. kimjr@med.yu.ac.kr
  • 5Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717, Korea.

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.

Keyword

hepatocyte growth factor; mitogen-activated protein kinases; neoplasm metastasis; urinary plasminogen activator

MeSH Terms

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
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