Diet-Derived Gallated Catechins Prevent TGF-ß-Mediated Epithelial-Mesenchymal Transition, Cell Migration and Vasculogenic Mimicry in Chemosensitive ES-2 Ovarian Cancer Cells.

Background: Transforming growth factor (TGF)-ß triggers ovarian cancer metastasis through epithelial-mesenchymal transition (EMT). Whereas drug design strategies targeting the TGF-ß signaling pathway have been envisioned, the anti-TGF structure:function aspect of chemopreventive diet-derived catechins remains unexplored.Aim: We assessed the effects of eight catechins on TGF-ß-mediated cell migration and induction of EMT biomarkers, as well as on In Vitro vasculogenic mimicry (VM), a process partly regulated by EMT-related transcription factors.Results: TGF-ß-mediated phosphorylation of Smad-3 and p38 signaling intermediates was more effective in a chemosensitive ES-2 ovarian cancer cell line but was inoperative in cis-platinum- and adriamycin-chemoresistant SKOV-3 ovarian cancer cells. Increases in cell migration and in gene/protein expression of EMT biomarkers Fibronectin, Snail, and Slug were observed in ES-2 cells. When VM was assessed in ES-2 cells, 3D capillary-like structures were formed and increases in EMT biomarkers found. Catechins bearing the galloyl moiety (CG, ECG, GCG, and EGCG) exerted potent inhibition of TGF-ß-induced cell migration as well as EMT, and inhibited VM, in part through inhibition of Snail and matrix metalloproteinase-2 secretion.Conclusions: Our data suggest that diet-derived catechins exhibit chemopreventive properties that circumvent the TGF-ß-mediated signaling which contributes to the ovarian cancer metastatic phenotype.

Functional targeting of the TGF-ßR1 kinase domain and downstream signaling: A role for the galloyl moiety of green tea-derived catechins in ES-2 ovarian clear cell carcinoma.

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)-ß-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-ß-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-ß-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-ß receptor (TGF-ßR1) kinase activity was supported by surface plasmon resonance assays showing direct physical interaction between TGF-ßR1 and the galloyl moiety. In silico molecular docking analysis predicted a model where galloylated catechins may bind TGF-ßR1 within its adenosine triphosphate binding cleft in a site analogous to that of Galunisertib, a selective adenosine triphosphate-mimetic competitive inhibitor of TGF-ßR1. 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-ßR1 in order to antagonize TGF-ß-mediated signaling that is required for ovarian cancer cell invasion and metastasis.