Theaflavin-3, 3'-digallate induces epidermal growth factor receptor downregulation

Black tea is one of the most popular beverages worldwide and especially in Western nations. Theaflavins, a mixture of theaflavin (TF-1), theaflavin-3-gallate (TF-2a), theaflavin-3'-gallate (TF-2b), and theaflavin-3,3'-digallate (TF-3) are the major components of black tea. Among these black tea components, theaflavin is generally considered to be the more effective component for the inhibition of carcinogenesis. Recently, TF-3 has been shown to have an anti proliferative effect on tumor cells, but the mechanism is not clear. in this study, we showed that TF-3-induced internalization and clownregulation of the epidermal growth factor receptor (EGFR). These results suggested that TF-3 induces EGFR endocytosis and degradation. We further showed that TF-3 stimulated EGFR ubiquitination and tyrosine kinase activation. Interestingly, TF-3-induced EGFR clownregulation is inhibited by the proteasome inhibitor, MG132, but not by the EGFR-specific receptor tyrosine kinase inhibitor, AG1478. Furthermore, pretreatment with TF-3 inhibited EGF-induced EGFR autophosphorylation, ERKs phosphorylation and AP-1 activation in JB6 C141 cells. In addition, TF-3 inhibited EGF-induced anchorage-independent cell transformation. Overall, our results indicate that TF3 might exert chemopreventive effects through the clownregulation of the EGFR. (c) 2005 Wiley-Liss, Inc.