Tang Feng-Yao, Chiang En-Pei Isabel, Shih Chung-Jin
Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung 40402, ROC Taiwan.
J Nutr Biochem. 2007 Jun;18(6):391-9. doi: 10.1016/j.jnutbio.2006.07.004. Epub 2006 Oct 17.
Angiogenesis, the formation of new blood vessels from preexisting capillaries, is essential for tumor progression and metastasis. During tumor neovascularization, vascular endothelial growth factor and ephrin (Eph) families emerge as critical mediators of angiogenesis. The green tea catechin epigallocatechin gallate (EGCG), a tyrosine kinase inhibitor, has been demonstrated in previous studies to be an effective antiangiogenesis agent. However, the inhibitory effect of green tea catechins on ephrin-A1-mediated tumor angiogenesis has not been demonstrated yet. Thus, in this study, we investigated the molecular mechanism of ephrin-A1-mediated cell migration and angiogenesis, as well as the inhibitory effects of EGCG. Here we show that ephrin-A1 mediates endothelial cell migration and regulates vascular remodeling in tumor neovascularization in vitro. We also demonstrated that ephrin-A1-mediated cell migration required the activation of extracellular-regulated kinase (ERK-1/2) but not of phosphatidylinositol-3-kinase. The green tea catechin EGCG inhibited ephrin-A1-mediated endothelial cell migration, as well as tumor angiogenesis, in a dose-dependent manner. Furthermore, EGCG inhibited the ephrin-A1-mediated phosphorylation of EphA2 and ERK-1/2. Taken together, these data indicated that activation of ERK-1/2 plays an essential role in ephrin-A1-mediated cell migration. EGCG inhibited ephrin-A1-mediated endothelial migration and angiogenesis. It suggests a novel antiangiogenesis application of EGCG in cancer chemoprevention.
血管生成是指从已有的毛细血管形成新的血管，这对于肿瘤的进展和转移至关重要。在肿瘤新生血管形成过程中，血管内皮生长因子和 Eph 家族成为血管生成的关键介质。绿茶儿茶素表没食子儿茶素没食子酸酯（EGCG）是一种酪氨酸激酶抑制剂，先前的研究已证明它是一种有效的抗血管生成剂。然而，绿茶儿茶素对 Ephrin-A1 介导的肿瘤血管生成的抑制作用尚未得到证实。因此，在本研究中，我们研究了 Ephrin-A1 介导的细胞迁移和血管生成的分子机制，以及 EGCG 的抑制作用。在这里我们表明，Ephrin-A1 在体外介导内皮细胞迁移并调节肿瘤新生血管形成中的血管重塑。我们还证明，Ephrin-A1 介导的细胞迁移需要细胞外调节激酶（ERK-1/2）的激活，而不需要磷脂酰肌醇-3-激酶的激活。绿茶儿茶素 EGCG 以剂量依赖性方式抑制 Ephrin-A1 介导的内皮细胞迁移以及肿瘤血管生成。此外，EGCG 抑制 Ephrin-A1 介导的 EphA2 和 ERK-1/2 的磷酸化。综上所述，这些数据表明 ERK-1/2 的激活在 Ephrin-A1 介导的细胞迁移中起重要作用。EGCG 抑制 Ephrin-A1 介导的内皮迁移和血管生成。这表明 EGCG 在癌症化学预防中具有一种新的抗血管生成应用。
