BACKGROUNDColon cancer is one of the major malignancies worldwide and it still remains resistant to much of the currently available chemotherapy. Downregulation of HGF/c-Met signaling pathway is an emerging therapy for cancer treatment.

METHODSIn this study, the inhibitory effects of c-Met phosphorylation were observed with SU11274 on different colon cancer cell lines in vitro.

RESULTSThe results revealed the significant inhibitory effects of SU11274 on cell proliferation and cell survival, in a time and dose-dependent manner. Furthermore, the inhibitory effects of SU11274 on different subgroups of colon cancer cells via the HGF/c-Met signaling pathway were implicated in this study.

CONCLUSIONThe results suggested the possible selective therapeutic effects of c-Met inhibitor on colon cancer.

Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Colonic Neoplasms ; drug therapy ; pathology ; Hepatocyte Growth Factor ; pharmacology ; Humans ; Indoles ; pharmacology ; Piperazines ; pharmacology ; Proto-Oncogene Proteins c-met ; antagonists & inhibitors ; physiology ; Signal Transduction ; Sulfonamides ; pharmacology

Antibodies, Monoclonal ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Drug Resistance, Neoplasm ; Humans ; Mutation ; Neoplasms ; metabolism ; therapy ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-met ; antagonists & inhibitors ; genetics ; metabolism ; Signal Transduction

Aberrant activation of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, is involved in the development and progression of many human cancers. In the cell-based screening assay, (-)epigallocatechin-3-gallate (EGCG) inhibited HGF/SF-Met signaling as indicated by its inhibitory activity on HGF/SF-induced cell scattering and uPA activation (IC50 = 15.8 microg/ml). Further analysis revealed that EGCG at low doses specifically inhibited HGF/SF-induced tyrosine phosphorylation of Met but not epidermal growth factor (EGF)-induced phosphorylation of EGF receptor (EGFR). On the other hand, high-dose EGCG decreased both Met and EGFR proteins. We also found that EGCG did not act on the intracellular portion of Met receptor tyrosine kinase, i.e., it inhibited InlB-dependent activation of Met but not NGF-induced activation of Trk-Met hybrid receptor. This inhibition decreased HGF-induced migration and invasion by parental or HGF/SF-transfected B16F10 melanoma cells in vitro in either a paracrine or autocrine manner. Furthermore, EGCG inhibited the invasion/metastasis of HGF/SF-transfected B16F10 melanoma cells in mice. Our data suggest the possible use of EGCG in human cancers associated with dysregulated paracrine or autocrine HGF/SF-Met signaling.
Animals ; Autocrine Communication/*drug effects ; Catechin/*analogs & derivatives/metabolism/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Female ; *Hepatocyte Growth Factor ; Humans ; Mice ; Mice, Inbred BALB C ; Neoplasms, Experimental/*metabolism/pathology ; Paracrine Communication/*drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-met/antagonists & inhibitors/metabolism ; Receptors, Growth Factor/antagonists & inhibitors/metabolism ; Signal Transduction

BACKGROUND: Up-regulation of the hepatocyte growth factor (HGF), its transmembrane tyrosine kinase receptor (c-Met), and urokinase type plasminogen activator (uPA), is associated with the development and metastasis of various types of cancers. However, the mechanisms by which HGF/c-Met signaling mediates cancer progression and metastasis are unclear. METHODS: We investigated the roles of HGF/c-Met in tumor progression and metastasis in NUGC-3 and MKN-28 stomach cancer cell lines. RESULTS: Treatment with HGF increased c-Met phosphorylation in a dose-dependent manner, as well as increasing cell proliferation. HGF treatment also increased the protein level and the activity of uPA in NUGC-3 and MKN-28 cells. A monoclonal antibody against human uPA receptor (uPAR), mAb 3936, inhibited HGF-mediated tumor cell invasion in a dose-dependent manner. Down-regulation of uPA using uPA-shRNA induced a decrease in in vitro cell invasion in NUGC-3 cells. CONCLUSIONS: These results suggest that NUGC-3 and MKN-28 cells express functional c-Met, which may provide a therapeutic target for interfering with metastases of cancer cells by inhibiting uPA and uPAR-mediated proteolysis.
Urinary Plasminogen Activator/antagonists & inhibitors/*metabolism ; Stomach Neoplasms/drug therapy/*enzymology ; Signal Transduction/*drug effects ; Receptors, Growth Factor/*drug effects ; Receptor Protein-Tyrosine Kinases/*drug effects ; Proto-Oncogene Proteins c-met/*drug effects ; Neoplasm Metastasis ; Humans ; Hepatocyte Growth Factor/*metabolism ; Disease Progression ; Adenocarcinoma/drug therapy/enzymology

OBJECTIVETo explore the signal pathway mediating the regulatory effect of Hepatitis B virus X protein (HBX) on c-met gene promoter in HepG2 cells.

METHODSThe expression of c-met in HBX-transfected HepG2 cells treated with different signal pathway inhibitors was detected by western blot, the invasion capability of cells was determined by Matrigel invasion assay.

RESULTSERK inhibitor U0126 inhibited the expression of the c-Met in HBx-transfected HepG2 cells. However, both p38MAPK inhibitor SB203580 and PI-3K inhibitor wortmanin had no effect on expression of the c-Met in HBx-transfected HepG2 cells. Furthermore, the ERK inhibitor U0126 also inhibited the invasiveness of HBX-transfected HepG2 cells.

CONCLUSIONHBx induces invasion of HCC via activation of ERK pathway.

Blotting, Western ; Butadienes ; pharmacology ; Extracellular Signal-Regulated MAP Kinases ; antagonists & inhibitors ; Gene Expression Regulation, Neoplastic ; Genetic Vectors ; Hep G2 Cells ; Hepatitis B virus ; genetics ; Humans ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Nitriles ; pharmacology ; Plasmids ; genetics ; Promoter Regions, Genetic ; genetics ; Proto-Oncogene Proteins c-met ; metabolism ; Signal Transduction ; Trans-Activators ; genetics ; metabolism ; Transfection