Abstract
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 microgram/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.
Highlights
The c-met protooncogene encodes a transmembrane glycoprotein, Met tyrosine kinase receptor (Naldini et al, 1991; Park et al, 1999), and the ligand for Met is hepatocyte growth factor, known as scatter factor (HGF/SF) (Bottaro et al, 1991)
While searching an herbal extract library obtained from Plant Extract Bank (Daejon, Korea) for a small molecule inhibitor of HGF/SF-Met signaling, we observed that the water extract of green tea EGCG inhibits HGF/SF-Met signaling 113 efficiently blocked the HGF/SF-induced activation of urokinase plasminogen activator (uPA) (Figure 1A, left panel)
Since EGCG is the major known bioactive polyphenol in green tea, we investigated whether EGCG inhibited HGF/Met signaling
Summary
The c-met protooncogene encodes a transmembrane glycoprotein, Met tyrosine kinase receptor (Naldini et al, 1991; Park et al, 1999), and the ligand for Met is hepatocyte growth factor, known as scatter factor (HGF/SF) (Bottaro et al, 1991) Both Met and HGF/SF are expressed in various tissues and signaling via this receptor-ligand pair affects a variety of biological activities, including cell growth (Nakamura et al, 1986), cellular motility (Stoker et al, 1987), angiogenesis (Bussolino et al, 1992), and morphogenesis (Tsarfaty et al, 1992). In many types of carcinoma, such as breast, gastric and colorectal cancers, overexpression of Met or HGF/SF predominates, resulting in the activation of HGF/SF-Met signaling in a paracrine manner (Jeffers et al, 1996; Birchmeier et al, 1997). The finding of activating mutants of Met in several human cancers such as renal papillary cancer (Schmidt et al, 1997), early-onset hepatoma (Park et al, 1999) and gastric adenocarcinoma (Lee et al, 2000) pro-
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