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Carcinogenesis Advance Access published online on July 3, 2009
Carcinogenesis, doi:10.1093/carcin/bgp166
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

(–)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAP kinase in colon cancer cells

Seiji Adachi1,2, Masahito Shimizu1, Yohei Shirakami1, Junichi Yamauchi2, Hideo Natsume2, Rie Matsushima-Nishiwaki2, Satoshi To3, I. Bernard Weinstein3, Hisataka Moriwaki1 and Osamu Kozawa2,*

1 Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
2 Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
3 Herbert Irving Comprehensive Cancer Center, Columbia University, Medical Center, NY 10032, USA

* Correspondence to Osamu Kozawa, Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan. Tel: +81-58-230-6214; Fax: +81-58-230-6215; E-mail: okozawa{at}gifu-u.ac.jp

We previously reported that (–)-epigallocatechin gallate (EGCG) in green tea alters plasma membrane organization and causes internalization of epidermal growth factor receptor (EGFR), resulting in the suppression of colon cancer cell growth. In the present study, we investigated the detailed mechanism underlying EGCG-induced downregulation of EGFR in SW480 colon cancer cells. Prolonged exposure to EGCG caused EGFR degradation. However, EGCG required neither an ubiquitin ligase (c-Cbl) binding to EGFR nor phosphorylation of EGFR at tyrosine residues, both of which are reportedly necessary for EGFR degradation induced by EGF. In addition, EGCG induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), a stress-inducible kinase believed to negatively regulate tumorigenesis, and the inhibition of p38 MAPK by SB203580, a specific p38 MAPK inhibitor, or the gene silencing using p38 MAPK-siRNA suppressed the internalization and subsequent degradation of EGFR induced by EGCG. EGFR underwent a gel mobility shift upon treatment with EGCG and this was canceled by SB203580, indicating that EGCG causes EGFR phosphorylation via p38 MAPK. Moreover, EGCG caused phosphorylation of EGFR at Ser1046/1047, a site which is critical for its downregulation and this was also suppressed by SB203580 or siRNA of p38 MAPK. Taken together, our results strongly suggest that phosphorylation of EGFR at serine 1046/1047 via activation of p38 MAPK plays a pivotal role in EGCG-induced downregulation of EGFR in colon cancer cells.

Key Words: EGCG • EGF receptor • downregulation • p38 MAPK

Received March 13, 2009; revised June 24, 2009; accepted June 24, 2009.


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