Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan, ROC.
Toxicol Appl Pharmacol. 2013 Nov 1;272(3):746-56. doi: 10.1016/j.taap.2013.07.019. Epub 2013 Aug 3.
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.
上皮间质转化（EMT）的分子基础可作为乳腺癌的潜在治疗靶点，因为 EMT 可能使乳腺肿瘤起始细胞获得类似干细胞的特性，并使乳腺癌细胞发生扩散。我们最近通过诱导细胞凋亡验证了白藜芦醇的天然甲氧基衍生物 3,5,4'-三甲氧基二苯乙烯（MR-3）在结直肠癌细胞异种移植中的抗肿瘤活性。还探索了 MR-3 对 EMT 和人 MCF-7 乳腺腺癌细胞系侵袭性的影响。我们发现，MR-3 显著增加上皮标志物 E-钙黏蛋白的表达，并引发 MCF-7 细胞呈现鹅卵石样形态，同时反向降低间充质标志物如 snail、slug 和波形蛋白的表达。与 EMT 逆转平行，MR-3 下调 MCF-7 细胞的侵袭和迁移。探讨 MR-3 抑制 EMT 和侵袭的作用机制表明，MR-3 显著降低β-连环蛋白的表达和核易位，伴随着β-连环蛋白靶基因的下调和膜结合β-连环蛋白的增加。这些结果表明 Wnt/β-连环蛋白信号通路参与了 MR-3 诱导的 MCF-7 细胞 EMT 逆转。值得注意的是，MR-3 通过抑制 Akt 的磷酸化来恢复糖原合酶激酶-3β的活性，Akt 的磷酸化是通过蛋白酶体介导的系统破坏β-连环蛋白所必需的。总体而言，这些发现表明，MR-3 对 MCF-7 细胞的抗侵袭活性可能是通过下调磷脂酰肌醇 3-激酶（PI3K）/AKT 信号通路，从而抑制β-连环蛋白核易位，从而抑制 EMT 来实现的。这些事件最终导致 EMT 的阻断和乳腺癌细胞的侵袭。
