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Chem Biol Interact. 2014 Jun 25;217:1-8. doi: 10.1016/j.cbi.2014.04.002. Epub 2014 Apr 12.

N-Hydroxycinnamide derivatives of osthole inhibit cell migration and invasion by suppressing Smad2 and Akt pathways in human colorectal adenocarcinoma cells.

Author information

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
2
Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
3
Division of Cardiology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Executive Yuan, Taoyuan, Taiwan; Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, Taiwan.
4
Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan; Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
5
Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
6
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: ycliang@tmu.edu.tw.

Abstract

WJ1376-1 and WJ1398-1 are new synthetic compounds developed based on the structure of the Chinese herbal medicine osthole. Previously, we reported that WJ1376-1 and WJ1398-1 can induce cell-cycle arrest by activating ATR kinase (ataxia telangiectasia and rad3 related kinase) and inhibiting the phosphorylation of Aurora A kinase. In this study, we determined that WJ1376-1 and WJ1398-1 strongly inhibited the migration and invasion in human colorectal cancer cells at concentrations as low as 1μM. In the transforming growth factor (TGF)-β-induced epithelial-mesenchymal transition model, WJ1376-1 and WJ1398-1 potently downregulated the transcription factor Snail1, the mesenchymal protein vimentin, and matrix metalloprotease-9, but upregulated the epithelial protein E-cadherin. WJ1376-1 and WJ1398-1 also inhibited the TGF-β-induced phosphorylation of Smad2 and of Akt at Ser 473, and the nuclear translocation of Smad2 was substantially lower in WJ1376-1- and WJ1398-1-treated cells than it was in control cells. In transient transfection experiments, we observed that WJ1376-1 and WJ1398-1 strongly inhibited TGF-β-stimulated activity of a Smad reporter. Finally, WJ1376-1 and WJ1398-1 blocked TGF-β-induced phosphorylation of the TGF-β Type I receptor (TGF-βRI). These results suggest that WJ1376-1 and WJ1398-1 inhibit cell migration and invasion by suppressing TGF-βRI phosphorylation and subsequently hindering both Smad2 and phosphatidylinositol 3-kinase/Akt signaling pathways.

KEYWORDS:

Akt; Invasion; Migration; Osthole; Smad; TGF-β

PMID:
24727557
DOI:
10.1016/j.cbi.2014.04.002
[Indexed for MEDLINE]

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