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 antiproliferative effect on tumor cells, but the mechanism is not clear. In this study, we showed that TF-3-induced internalization and downregulation 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 downregulation 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 Cl41 cells. In addition, TF-3 inhibited EGF-induced anchorage-independent cell transformation. Overall, our results indicate that TF-3 might exert chemopreventive effects through the downregulation of the EGFR.
Mizuno
Hideya
H
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Cho
Yong-Yeon
YY
Zhu
Feng
F
Ma
Wei-Ya
WY
Bode
Ann M
AM
Yang
Chung S
CS
Ho
Chi-Tang
CT
Dong
Zigang
Z
D044946:Biflavonoids / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D002392:Catechin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics*; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D010957:Plasmids; D013662:Tea; D014162:Transfection
D044946:Biflavonoids; D013662:Tea; C077197:theaflavin digallate; D005707:Gallic Acid; D002392:Catechin; D066246:ErbB Receptors