Graduate Thesis Or Dissertation
 

Suppression of Met signaling by the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG)

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  • Met is a prognostic indicator of colorectal cancer patient survival. Therapies that target Met may therefore have beneficial outcomes in the clinic. Recently, EGCG was reported to suppress Met activation, although the mechanisms were not elucidated. HCT116 and HT29 human colon cancer cells were used to examine the relationships between Met activation, EGCG treatment, and H₂O₂ generation. At concentrations of 0.5, 1 and 5 μM, EGCG suppressed the activation of Met induced by its ligand, hepatocyte growth factor (HGF). Concentrations of 10 μM EGCG and below generated low amounts of H₂O₂ (<1.5 μM), whereas higher H₂O₂ concentrations (>5 μM) were required to directly increase the phosphorylation of Met. Moreover, suppression of Met activation by EGCG occurred in the presence or absence of catalase, suggesting that such effects were not an "artifact" of H₂O₂ generated from EGCG in cell culture media. Molecular docking and enzyme kinetic analyses suggested that EGCG is a competitive inhibitor, binding to the kinase domain of Met with a Ki of 3.3 μM EGCG. The downstream effect of EGCG mediated suppression of the Met receptor included decreased signaling to members of the MAPK and PI3KK signaling pathways. Cell proliferation and migration was also significantly inhibited by EGCG. Overall, the data presented in this dissertation support that EGCG is able to suppress HGF-induced Met signaling. These findings demonstrate that EGCG might be a beneficial therapeutic agent in the colon, inhibiting Met signaling and helping to attenuate tumor metastasis.
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