title: N-Hydroxycinnamide derivatives of osthole inhibit cell migration and invasion by suppressing Smad2 and Akt pathways in human colorectal adenocarcinoma cells.
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.
authors.affiliation: 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.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Feng-Ming
authors.initials: FM
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Ren-Jye
authors.initials: RJ
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Shyr-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Fat-Moon
authors.initials: FM
authors.lastname: Suk
authors.affiliation: 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.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003374:Coumarins / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D003374:Coumarins; D006877:Hydroxamic Acids; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C000588914:WJ1376-1; C000588915:WJ1398-1; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Akt; Invasion; Migration; Osthole; Smad; TGF-β