Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Chem Biol Interact. 2010 May 14;185(3):247-52. doi: 10.1016/j.cbi.2010.03.036. Epub 2010 Mar 25.
(-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, inhibits the growth of colorectal cancer cells by inhibiting the activation of various types of receptor tyrosine kinases (RTKs). The RTK vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis induces tumor angiogenesis in colorectal cancer. This study examined the effects of EGCG on the activity of the VEGF/VEGFR axis and the expression of hypoxia-inducible factor (HIF)-1alpha, which promotes angiogenesis by elevating VEGF levels, in human colorectal cancer cells. Total and phosphorylated (i.e., activated) form (p-VEGFR-2) of VEGFR-2 proteins were overexpressed in a series of human colorectal cancer cell lines. Within 3h, EGCG caused a decrease in the expression of HIF-1alpha protein and VEGF, HIF-1alpha, insulin-like growth factor (IGF)-1, IGF-2, epidermal growth factor (EGF), and heregulin mRNAs in SW837 colorectal cancer cells, which express a constitutively activated VEGF/VEGFR axis. A decrease was also observed in the expression of VEGFR-2, p-VEGFR-2, p-IGF-1 receptor, p-ERK, and p-Akt proteins within 6h after EGCG treatment. Drinking EGCG significantly inhibited the growth of SW837 xenografts in nude mice, and this was associated with the inhibition of the expression and activation of VEGFR-2. The consumption of EGCG also inhibited activation of ERK and Akt, both of which are downstream signaling molecules of the VEGF/VEGFR axis, and reduced the expression of VEGF mRNA in xenografts. These findings suggest that EGCG may exert, at least in part, growth-inhibitory effects on colorectal cancer cells by inhibiting the activation of the VEGF/VEGFR axis through suppressing the expression of HIF-1alpha and several major growth factors. EGCG may therefore be useful in the chemoprevention and/or treatment of colorectal cancer.
(-)-表没食子儿茶素没食子酸酯（EGCG）是绿茶的主要成分，通过抑制各种类型的受体酪氨酸激酶（RTKs）的激活来抑制结直肠癌细胞的生长。RTK 血管内皮生长因子（VEGF）/VEGF 受体（VEGFR）轴诱导结直肠癌细胞中的肿瘤血管生成。本研究检查了 EGCG 对 VEGF/VEGFR 轴的活性和缺氧诱导因子（HIF）-1α的表达的影响，HIF-1α 通过提高 VEGF 水平促进血管生成，在人结直肠癌细胞中。一系列人结直肠癌细胞系中 VEGFR-2 蛋白的总形式和磷酸化形式（即激活形式，p-VEGFR-2）过表达。在 3 小时内，EGCG 导致表达的 HIF-1α 蛋白和 VEGF、HIF-1α、胰岛素样生长因子（IGF）-1、IGF-2、表皮生长因子（EGF）和 heregulin mRNA 在表达组成性激活的 VEGF/VEGFR 轴的 SW837 结直肠癌细胞中减少。在用 EGCG 处理后 6 小时内，也观察到 VEGFR-2、p-VEGFR-2、p-IGF-1 受体、p-ERK 和 p-Akt 蛋白的表达减少。在裸鼠中，EGCG 显著抑制 SW837 异种移植物的生长，这与 VEGFR-2 的表达和激活的抑制有关。EGCG 的消耗还抑制了 ERK 和 Akt 的激活，它们都是 VEGF/VEGFR 轴的下游信号分子，并减少了异种移植物中 VEGF mRNA 的表达。这些发现表明，EGCG 通过抑制 HIF-1α 和几种主要生长因子的表达来抑制 VEGF/VEGFR 轴的激活，从而对结直肠癌细胞发挥至少部分生长抑制作用。因此，EGCG 可用于结直肠癌的化学预防和/或治疗。
