The green tea catechins, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells
The green tea catechins, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG), inhibit HGF/Met signaling in immortalized and tumorigenic breast epithelial cells
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DOI：
10.1038/sj.onc.1209227
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发表时间：
2006-03-23
期刊：
影响因子：
8
通讯作者：
Cardelli, JA
中科院分区：
文献类型：
--
作者：
Bigelow, RLH;Cardelli, JA
肝细胞生长因子（HGF）受体Met是乳腺癌患者预后和生存的一个强有力的预后指标，表明靶向Met的治疗可能在临床上具有有益的结果。（-）表没食子儿茶素-3-没食子酸酯（EGCG）是一种在绿色茶中发现的儿茶素，已被认为是一种潜在的治疗剂。我们评估了EGCG在永生化的非致瘤性乳腺细胞系MCF 10A和侵袭性乳腺癌细胞系MDA-MB-231中抑制HGF信号传导的能力。在两种细胞系中，HGF处理诱导Met、ERK和AKT的快速、持续活化。预处理细胞的浓度低至0.3 μ M的EGCG抑制HGF诱导的Met磷酸化和下游激活的AKT和ERK。用5.0 μ M的EGCG治疗阻断了HGF诱导细胞运动和侵袭的能力。我们评估了替代性绿色茶儿茶素抑制HGF诱导的信号传导和运动的能力。（-）-表儿茶素-3-没食子酸酯（ECG）的功能类似于EGCG，在MCF 10A细胞中，在低至0.6 μ M时完全阻断HGF诱导的信号传导，在5 μ M时完全阻断运动性;而（-）-表儿茶素（EC）在任何测试浓度下都不能抑制HGF诱导的事件。(-)-表没食子儿茶素（EGC），但是，完全抑制HGF诱导的AKT和ERK磷酸化浓度为10和20 μ M，但不能阻断Met激活。尽管有这些观察结果，EGC在10 μ M时确实抑制MCF 10A细胞中HGF诱导的运动性。这些观察结果表明，R1没食子酰基和R2羟基在介导绿色茶儿茶素对HGF/Met信号传导的抑制作用中是重要的。这些结合的体外研究揭示了绿色茶多酚作为癌症治疗剂抑制Met信号传导并潜在地阻断侵袭性癌症生长的可能益处。
The hepatocyte growth factor (HGF) receptor, Met, is a strong prognostic indicator of breast cancer patient outcome and survival, suggesting that therapies targeting Met may have beneficial outcomes in the clinic. (-)Epigallocatechin- 3-gallate ( EGCG), a catechin found in green tea, has been recognized as a potential therapeutic agent. We assessed the ability of EGCG to inhibit HGF signaling in the immortalized, nontumorigenic breast cell line, MCF10A, and the invasive breast carcinoma cell line, MDA-MB-231. HGF treatment in both cell lines induced rapid, sustained activation of Met, ERK and AKT. Pretreatment of cells with concentrations of EGCG as low as 0.3 mu M inhibited HGF-induced Met phosphorylation and downstream activation of AKT and ERK. Treatment with 5.0 mu M EGCG blocked the ability of HGF to induce cell motility and invasion. We assessed the ability of alternative green tea catechins to inhibit HGF induced signaling and motility. (-)-Epicatechin-3-gallate ( ECG) functioned similar to EGCG by completely blocking HGF-induced signaling as low as 0.6 mu M and motility at 5 mu M in MCF10A cells; whereas, (-)- epicatechin (EC) was unable to inhibit HGF-induced events at any concentration tested. (-)- Epigallocatechin ( EGC), however, completely repressed HGF-induced AKT and ERK phosphorylation at concentrations of 10 and 20 mu M, but was incapable of blocking Met activation. Despite these observations, EGC did inhibit HGF-induced motility in MCF10A cells at 10 mu M. These observations suggest that the R1 galloyl and the R2 hydroxyl groups are important in mediating the green tea catechins' inhibitory effect towards HGF/Met signaling. These combined in vitro studies reveal the possible benefits of green tea polyphenols as cancer therapeutic agents to inhibit Met signaling and potentially block invasive cancer growth.