TY - JOUR
T1 - Theaflavin-3, 3′-digallate induces epidermal growth factor receptor downregulation
AU - Mizuno, Hideya
AU - Cho, Yong Yeon
AU - Zhu, Feng
AU - Ma, Wei Ya
AU - Bode, Ann M.
AU - Yang, Chung S.
AU - Ho, Chi Tang
AU - Dong, Zigang
PY - 2006/3
Y1 - 2006/3
N2 - 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-Za), 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 CI41 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.
AB - 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-Za), 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 CI41 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.
KW - A431 human epidermoid carcinoma
KW - Anchorage-independent cell transformation
KW - JB6 CI41 mouse epidermal cells
KW - Theaflavins
UR - http://www.scopus.com/inward/record.url?scp=33644824234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644824234&partnerID=8YFLogxK
U2 - 10.1002/mc.20174
DO - 10.1002/mc.20174
M3 - Article
C2 - 16353237
AN - SCOPUS:33644824234
SN - 0899-1987
VL - 45
SP - 204
EP - 212
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 3
ER -