Carcinogenesis Advance Access originally published online on June 26, 2008
Carcinogenesis 2008 29(10):1986-1993; doi:10.1093/carcin/bgn128
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(–)-Epigallocatechin gallate causes internalization of the epidermal growth factor receptor in human colon cancer cells
1 Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, HHSC-1509, 701 West 168th Street, New York, NY 10032-2704, USA
2 Department of Gastroenterology
3 Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
4 Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA
* To whom correspondence should be addressed. Tel: +1 212 305 6921; Fax: +1 212 305 6889; Email: ibw1{at}columbia.edu
We recently found that the inhibitory effect of (–)-epigallocatechin gallate (EGCG) on epidermal growth factor (EGF) binding to the epidermal growth factor receptor (EGFR) is associated with alterations in lipid organization in the plasma membrane of colon cancer cells. Since changes in lipid organizations are thought to play a role in the trafficking of several membrane proteins, in this study we examined the effects of EGCG on cellular localization of the EGFR in SW480 cells. Treatment of the cells for 30 min with as little as 1 µg/ml of EGCG caused a decrease in cell surface-associated EGFRs and this was associated with internalization of EGFRs into endosomal vesicles. Similar effects were seen with a green fluorescent protein (GFP)–EGFR fusion protein. As expected, the EGFR protein was phosphorylated at tyrosine residues, ubiquitinated and partially degraded when the cells were treated with EGF, but treatment with EGCG caused none of these effects. The loss of EGFRs from the cell surface induced by treating the cells with EGF for 30 min persisted for at least 2 h. However, the loss of EGFRs from the cell surface induced by temporary exposure to EGCG was partially restored within 1–2 h. These studies provide the first evidence that EGCG can induce internalization of EGFRs into endosomes, which can recycle back to the cell surface. This sequestrating of inactivated EGFRs into endosomes may explain, at least in part, the ability of EGCG to inhibit activation of the EGFR and thereby exert anticancer effects.
Abbreviations: BSA, bovine serum albumin; DMEM, Dulbecco’s modified Eagle’ medium; EEA1, early endosome antigen-1; EC, epicatechin; EGCG, epigallocatechin gallate; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbent assay; GFP, green fluorescent protein; RTK, receptor tyrosine kinase; SOD, superoxide dismutase
Received February 12, 2008; revised May 15, 2008; accepted May 19, 2008.
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  S. Adachi, M. Shimizu, Y. Shirakami, J. Yamauchi, H. Natsume, R. Matsushima-Nishiwaki, S. To, I.B. Weinstein, H. Moriwaki, and O. Kozawa (-)-Epigallocatechin gallate downregulates EGF receptor via phosphorylation at Ser1046/1047 by p38 MAPK in colon cancer cells Carcinogenesis, September 1, 2009; 30(9): 1544 - 1552. [Abstract] [Full Text] [PDF]
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