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Functional targeting of the TGF-βR1 kinase domain and downstream signaling: A role for the galloyl moiety of green tea-derived catechins in ES-2 ovarian clear cell carcinoma
The Journal of Nutritional Biochemistry ( IF 4.8 ) Pub Date : 2020-10-02 , DOI: 10.1016/j.jnutbio.2020.108518
Audrey-Ann Sicard 1 , Narjara Gonzalez Suarez 1 , Laurent Cappadocia 2 , Borhane Annabi 1
Affiliation  

The galloyl moiety is a specific structural feature which dictates, in part, the chemopreventive properties of diet-derived catechins. In ovarian cancer cells, galloylated catechins were recently demonstrated to target the transforming growth factor (TGF)-β-mediated control of the epithelial-mesenchymal transition process. The specific impact of the galloyl moiety on such signaling, however, remains poorly understood. Here, we questioned whether the sole galloyl moiety interacted with TGF-β-receptors to alter signal transduction and chemotactic migratory response in an ES-2 serous carcinoma-derived ovarian cancer cell model. In line with the LogP and LogS values of the tested molecules, we found that TGF-β-induced Smad-3 phosphorylation and cell migration were optimally inhibited, provided that the lateral aliphatic chain of the galloyl moiety reached 8–10 carbons. Functional inhibition of the TGF-β receptor (TGF-βR1) kinase activity was supported by surface plasmon resonance assays showing direct physical interaction between TGF-βR1 and the galloyl moiety. In silico molecular docking analysis predicted a model where galloylated catechins may bind TGF-βR1 within its adenosine triphosphate binding cleft in a site analogous to that of Galunisertib, a selective adenosine triphosphate-mimetic competitive inhibitor of TGF-βR1. In conclusion, our data suggest that the galloyl moiety of the diet-derived catechins provides specificity of action to galloylated catechins by positioning them within the kinase domain of the TGF-βR1 in order to antagonize TGF-β-mediated signaling that is required for ovarian cancer cell invasion and metastasis.



中文翻译:

TGF-βR1 激酶结构域和下游信号的功能靶向:绿茶衍生儿茶素的没食子酰部分在 ES-2 卵巢透明细胞癌中的作用

没食子酰部分是一种特定的结构特征,部分决定了饮食衍生的儿茶素的化学预防特性。在卵巢癌细胞中,最近证明没食子酰化儿茶素靶向转化生长因子 (TGF)-β 介导的上皮间充质转化过程控制。然而,人们对没食子酰部分对这种信号传导的具体影响仍然知之甚少。在这里,我们质疑唯一的没食子酰基部分是否与 TGF-β-受体相互作用以改变 ES-2 浆液性癌衍生的卵巢癌细胞模型中的信号转导和趋化迁移反应。与测试分子的 LogP 和 LogS 值一致,我们发现 TGF-β 诱导的 Smad-3 磷酸化和细胞迁移受到最佳抑制,假设没食子酰基部分的侧脂肪链达到 8-10 个碳。TGF-β 受体 (TGF-βR1) 激酶活性的功能性抑制得到了表面等离子体共振分析的支持,该分析显示 TGF-βR1 和没食子酰部分之间的直接物理相互作用。计算机分子对接分析预测了一个模型,其中没食子酰化的儿茶素可以在其三磷酸腺苷结合间隙内结合 TGF-βR1,该间隙与 Galunisertib 类似,Galunisertib 是 TGF-βR1 的选择性三磷酸腺苷模拟竞争抑制剂。总之,我们的数据表明,饮食来源的儿茶素的没食子酰部分通过将它们定位在 TGF-βR1 的激酶结构域内为没食子酰化的儿茶素提供特异性作用,以拮抗卵巢所需的 TGF-β 介导的信号传导。癌细胞侵袭和转移。

更新日期:2020-10-30
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