Department of Biochemistry, Ajou University Medical School, Suwon, Korea.
Exp Mol Med. 2011 Feb 28;43(2):111-20. doi: 10.3858/emm.2011.43.2.013.
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.
肝细胞生长因子/分散因子（HGF/SF）及其受体 Met 的异常激活与许多人类癌症的发生和发展有关。在基于细胞的筛选试验中，（-）表没食子儿茶素-3-没食子酸酯（EGCG）通过抑制 HGF/SF 诱导的细胞分散和 uPA 激活来抑制 HGF/SF-Met 信号（IC50=15.8μg/ml）。进一步分析表明，EGCG 在低剂量时特异性抑制 HGF/SF 诱导的 Met 酪氨酸磷酸化，但不抑制表皮生长因子（EGF）诱导的 EGF 受体（EGFR）磷酸化。另一方面，高剂量的 EGCG 降低了 Met 和 EGFR 蛋白的水平。我们还发现 EGCG 不作用于 Met 受体酪氨酸激酶的细胞内部分，即它抑制 InlB 依赖性 Met 的激活，但不抑制 NGF 诱导的 Trk-Met 杂合受体的激活。这种抑制作用以旁分泌或自分泌的方式降低了亲本或 HGF/SF 转染的 B16F10 黑色素瘤细胞在体外迁移和侵袭的能力。此外，EGCG 抑制了 HGF/SF 转染的 B16F10 黑色素瘤细胞在小鼠中的侵袭/转移。我们的数据表明，EGCG 可能用于与失调的旁分泌或自分泌 HGF/SF-Met 信号有关的人类癌症。
