Angiogenesis, the formation of new blood vessels from pre-existing capillaries, is essential for tumor progression and metastasis. Recent studies showed that the VEGF modulates the expression of ephrin A1 and mediates the activation of Eph A2 to regulate vascular remodeling in tumor neovascularization. Furthermore, activation of EphA2 modulated by ephrin A1 is required for the cell migration and sprouting of blood vessels during tumor neovascularization. It suggested an essential role of EphA2 receptor activation during tumor angiogenesis. Green tea catechin, epigallocatechin gallate (EGCG), a tyrosine kinase inhibitor, has been demonstrated as an effective anti-angiogenesis agent in previous studies. However, the inhibitory effect of green tea catechins on ephrin A1- mediated endothelial cell migration has not been demonstrated yet. Thus, we investigated the molecular mechanism of ephrin A1/Eph A2-stimulated cell migration and the inhibitory effects of EGCG in this study. Here we show that green tea catechin, EGCG, inhibited ephrin A1 -mediated endothelial cell migration and blocked the activation of Eph A2 during tumor angiogenesis. Ephrin A1- mediated cell migration required the activation of extracellular -regulated kinase (ERK-1/2) but not phosphatidylinositol-3-kinase (PI-3K). Furthermore, we demonstrate that EGCG inhibited EphA2-mediated migration of endothelial cells by blocking the activation of ERK-1/2. Take together, these data indicated that ERK-1/2 protein as a potential new target for the therapeutic intervention in ephrin A1- mediated endothelial migration and a novel role of EGCG in anti-angiogenesis application.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]