A green tea component suppresses posttranslational expression of basic fibroblast growth factor in colorectal cancer
A green tea component suppresses posttranslational expression of basic fibroblast growth factor in colorectal cancer
复制标题
DOI：
10.1053/j.gastro.2008.02.095
复制
发表时间：
2008-06-01
期刊：
影响因子：
29.4
通讯作者：
Baek, Seung Joon
中科院分区：
文献类型：
--
作者：
Sukhthankar, Mugdha;Yamaguchi, Kiyoshi;Baek, Seung Joon
背景与目的：绿色茶儿茶素具有抗癌作用。表没食子儿茶素-3-没食子酸酯（EGCG）占绿色茶提取物中总儿茶素含量的近50%，具有非常有效的抗氧化作用。EGCG还可能通过抑制促血管生成因子（包括血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF））来抑制血管生成，这反过来又抑制肿瘤生长和转移。然而，EGCG抑制bFGF表达的确切分子机制尚不清楚。我们的目的是阐明EGCG抑制大肠癌bFGF表达的分子机制。方法：我们研究了人大肠癌中EGCG对bFGF的翻译后调节。癌细胞我们还研究了碱性成纤维细胞生长因子在肠肿瘤形成的APC（分钟）/（+）小鼠和儿茶素治疗。结果：bFGF蛋白在EGCG存在下迅速降解，但蛋白酶体抑制剂抑制这种降解。还发现EGCG增加bFGF的泛素化和20 S蛋白酶体的胰蛋白酶样活性，从而导致bFGF蛋白的降解。此外，与载体治疗的小鼠相比，EGCG抑制APC（Min）/（+）小鼠中的肿瘤形成，与bFGF表达减少相关。结论：泛素-蛋白酶体降解途径是EGCG下调bFGF表达的重要机制。猫echin化合物具有比化疗剂更少的副作用，因此可以用作癌症治疗中的概念验证，以通过靶向蛋白质如bFGF来抑制生长和转移。
Background & Aims: Green tea catechins are known to have anticarcinogenic effects. Epigallocatechin-3-gallate (EGCG) accounts for almost 50% of the total catechin content in green tea extract and has very potent antioxidant effects. EGCG also inhibits angiogenesis, possibly through the inhibition of proangiogenic factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn, inhibits tumor growth and metastasis. However, the exact molecular mechanism by which EGCG suppresses bFGF expression is not known. Our objective was to elucidate the molecular mechanisms by which EGCG inhibits bFGF expression in colorectal cancer. Methods: We examined posttranslational regulation of bFGF by EGCG in human colorectal. cancer cells. We also examined bFGF in intestinal tumor formation of APC(Min)/(+) mice with and without catechin treatment. Results: The bFGF protein was quickly degraded in the presence of EGCG, but a proteasome inhibitor suppressed this degradation. EGCG was also found to increase ubiquitination of bFGF and trypsin-like activity of the 20S proteasome, thereby resulting in the degradation of bFGF protein. Furthermore, EGCG suppressed tumor formation in APC(Min)/(+) mice, compared with vehicle-treated mice, in association with reduced bFGF expression. Conclusions: The ubiquitin-proteasome degradation pathway contributes significantly to down-regulation of bFGF expression by EGCG. Cat echin compounds have fewer adverse effects than chemotherapeutic agents and hence can be used as proof-of-concept in cancer therapeutics to suppress growth and metastasis by targeting proteins such as bFGF.