期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 272, 期 3, 页码 746-756出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2013.07.019
关键词
Epithelial-mesenchymal transition (EMT); 3,5,4 '-Trimethoxystilbene (MR-3); E-cadherin; beta-Catenin; Glycogen synthase kinase (GSK)-3 beta
资金
- National Science Council, Republic of China [NSC 97-2320-B-040-015-MY3, NSC 100-2320-B-040-009-MY3]
The molecular basis of epithelial-mesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4'-trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of beta-catenin, accompanied with the downregulation of beta-catenin target genes and the increment of membrane-bound beta-catenin. These results suggest the involvement of Wnt/beta-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3 beta activity by inhibiting the phosphorylation of Akt, the event required for beta-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, beta-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. (C) 2013 Elsevier Inc. All rights reserved.
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