1. Academic Validation
  2. 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

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

  • J Nutr Biochem. 2021 Jan;87:108518. doi: 10.1016/j.jnutbio.2020.108518.
Audrey-Ann Sicard 1 Narjara Gonzalez Suarez 1 Laurent Cappadocia 2 Borhane Annabi 3
Affiliations

Affiliations

  • 1 Laboratoire d'Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada.
  • 2 Laboratoire de Biochimie Analytique et Structurale, Centre de recherche CERMO-FC, Université du Québec à Montréal, Montreal, Quebec, Canada.
  • 3 Laboratoire d'Oncologie Moléculaire, Département de Chimie, Université du Québec à Montréal, Montreal, Quebec, Canada. Electronic address: [email protected].
Abstract

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.

Keywords

Catechins; Epithelial-mesenchymal transition; Green tea; Ovarian cancer; Transforming growth factor.

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