Kumar K J Senthil, Vani M Gokila, Chueh Pin-Ju, Mau Jeng-Leun, Wang Sheng-Yang
Department of Forestry, National Chung Hsing University, Taichung, Taiwan.
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan.
PLoS One. 2015 Feb 6;10(2):e0117111. doi: 10.1371/journal.pone.0117111. eCollection 2015.
Epithelial-to-mesenchymal transition (EMT) is a crucial event involved metastasis of certain tumors. Thus, identifying chemical agents that can block EMT is highly warranted for the development of anti-cancer chemoprevention/chemotherapies. In this study, we found that Antrodin C (ADC), a maleimide derivative isolated from Antrodia cinnamomea health food product inhibits TGF-β1-induced EMT and breast cancer cell metastasis in vitro. Pretreatment of MCF-7 cells with ADC significantly blocked TGF-β1-induced phenotypic changes and actin cytoskeleton remodeling. In addition, ADC was able to up-regulate epithelial markers such as E-cadherin and occludin, whereas mesenchymal markers including N-cadherin and vimentin were significantly inhibited, possibly through the modulation of transcriptional regulators Smad/Smad3. ADC blocked TGF-β1-induced migration and invasion of MCF-7 cells through the down-regulation of matrix-metalloproteinases (MMP-2, -9) and urokinase plasminogen activator (uPA). The inhibition of MMPs and uPA activity by ADC was reasoned by suppression of its corresponding transcription factor β-catenin. Taken together, our data suggested that ADC attenuates the TGF-β1-induced EMT, migration and invasion of human breast carcinoma through the suppression of Smad2/3 and β-catenin signaling pathways.
上皮-间质转化（EMT）是某些肿瘤转移过程中的关键事件。因此，开发抗癌化学预防/化疗药物时，非常有必要鉴定能够阻断EMT的化学试剂。在本研究中，我们发现从樟芝健康食品中分离得到的马来酰亚胺衍生物安络小皮伞素C（ADC）在体外可抑制TGF-β1诱导的EMT和乳腺癌细胞转移。用ADC预处理MCF-7细胞可显著阻断TGF-β1诱导的表型变化和肌动蛋白细胞骨架重塑。此外，ADC能够上调上皮标志物如E-钙黏蛋白和闭合蛋白，而包括N-钙黏蛋白和波形蛋白在内的间质标志物则受到显著抑制，这可能是通过调节转录调节因子Smad/Smad3实现的。ADC通过下调基质金属蛋白酶（MMP-2、-9）和尿激酶型纤溶酶原激活剂（uPA）来阻断TGF-β1诱导的MCF-7细胞迁移和侵袭。ADC对MMPs和uPA活性的抑制作用是通过抑制其相应的转录因子β-连环蛋白来实现的。综上所述，我们的数据表明，ADC通过抑制Smad2/3和β-连环蛋白信号通路，减弱了TGF-β1诱导的人乳腺癌细胞的EMT、迁移和侵袭。
