Antrodin C inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via suppression of Smad2/3 and β-catenin signaling pathways

K J Senthil Kumar; M Gokila Vani; Pin-Ju Chueh; Jeng-Leun Mau; Sheng-Yang Wang

doi:10.1371/journal.pone.0117111

Antrodin C inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via suppression of Smad2/3 and β-catenin signaling pathways

PLoS One. 2015 Feb 6;10(2):e0117111. doi: 10.1371/journal.pone.0117111. eCollection 2015.

Authors

K J Senthil Kumar¹, M Gokila Vani¹, Pin-Ju Chueh², Jeng-Leun Mau³, Sheng-Yang Wang⁴

Affiliations

¹ Department of Forestry, National Chung Hsing University, Taichung, Taiwan.
² Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan.
³ Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan; National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan.
⁴ Department of Forestry, National Chung Hsing University, Taichung, Taiwan; National Chung Hsing University/University of California at Davis, Plant and Food Biotechnology Center, National Chung Hsing University, Taichung, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / drug effects
Actin Cytoskeleton / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / isolation & purification
Antineoplastic Agents / pharmacology*
Antrodia / chemistry
Antrodia / metabolism
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cadherins / metabolism
Cell Movement / drug effects
Cell Survival / drug effects
Down-Regulation / drug effects
Epithelial-Mesenchymal Transition / drug effects*
Female
Humans
MCF-7 Cells
Maleimides / chemistry
Maleimides / isolation & purification
Maleimides / pharmacology*
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Signal Transduction / drug effects*
Smad2 Protein / metabolism
Smad3 Protein / metabolism
Transforming Growth Factor beta1 / pharmacology
Up-Regulation / drug effects

Substances

Antineoplastic Agents
Cadherins
Maleimides
Smad2 Protein
Smad3 Protein
Transforming Growth Factor beta1
antrodin C
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9

Grants and funding

This study was supported by the National Science Council, Republic of China (NSC-102-2911-I-005-301, NSC-103-2911-I-005-301), and the Ministry of Education, Taiwan, ROC, under the ATU plan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.