3,5,4′-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/β-catenin signaling cascades and reversal of epithelial–mesenchymal transition

• Published in: Toxicology and applied pharmacology 2013-11, Vol.272 (3), p.746-756
• Main Authors: Tsai, Jie-Heng, Hsu, Li-Sung, Lin, Chih-Li, Hong, Hui-Mei, Pan, Min-Hsiung, Way, Tzong-Der, Chen, Wei-Jen
• Format: Article
• Language: English
• Subjects: 3,5,4′-Trimethoxystilbene (MR-3); 60 APPLIED LIFE SCIENCES; Anticarcinogenic Agents - chemistry; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; APOPTOSIS; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; CARCINOMAS; Cell Line, Tumor; Down-Regulation - drug effects; Down-Regulation - physiology; E-cadherin; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - physiology; Epithelial–mesenchymal transition (EMT); Female; GENES; GLYCOGEN; Glycogen synthase kinase (GSK)-3β; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; MAMMARY GLANDS; MCF-7 Cells; Medical sciences; MEMBRANES; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness - prevention & control; Oncogene Protein v-akt - antagonists & inhibitors; Oncogene Protein v-akt - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PHOSPHORYLATION; SIGNALS; Stilbenes - chemistry; Stilbenes - pharmacology; Stilbenes - therapeutic use; Toxicology; TRANSLOCATION; Tumors; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - physiology; β-Catenin
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.07.019

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 β-catenin, accompanied with the downregulation of β-catenin target genes and the increment of membrane-bound β-catenin. These results suggest the involvement of Wnt/β-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3β activity by inhibiting the phosphorylation of Akt, the event required for β-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, β-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. •MR-3 blocked MCF-7 cell invasion by inducing a reversal of EMT.•Wnt/β-catenin signaling is involved in MR-3-induced EMT reversion of MCF-7 cells.•Knockdown of β-catenin was sufficient to restore epithelial marker E-cadherin levels.•MR-3 recovered the function of GSK-3β that inhibits β-catenin nuclear translocation.