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.
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.
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC.
Jie-Heng
JH
Tsai
Li-Sung
LS
Hsu
Chih-Li
CL
Lin
Hui-Mei
HM
Hong
Min-Hsiung
MH
Pan
Tzong-Der
TD
Way
Wei-Jen
WJ
Chen
D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077185:Resveratrol; D013267:Stilbenes; D051176:beta Catenin; C497286:3,4',5-trimethoxystilbene; C495270:CTNNB1 protein, human
3,5,4′-Trimethoxystilbene (MR-3); E-cadherin; Epithelial–mesenchymal transition (EMT); Glycogen synthase kinase (GSK)-3β; β-Catenin