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 1 μM. 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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalChemico-Biological Interactions
Volume217
DOIs
Publication statusPublished - Jun 25 2014

Fingerprint

Cell Movement
Transforming Growth Factors
Adenocarcinoma
Derivatives
Phosphorylation
Cells
Phosphotransferases
Aurora Kinase A
Phosphatidylinositol 3-Kinase
WJ1376-1
osthol
WJ1398-1
Ataxia Telangiectasia
Epithelial-Mesenchymal Transition
Herbal Medicine
Metalloproteases
Vimentin
Cadherins
Cell Cycle Checkpoints
Transfection

Keywords

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

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{3654cd2f84464e6e8bf9c28cb39e9e38,
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 1 μM. 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",
author = "Liu, {Ling Yu} and Huang, {Wei Jan} and Ho, {Feng Ming} and Ren-Jye Lin and Lin, {Shyr Yi} and Suk, {Fat Moon} and Liang, {Yu Chih}",
year = "2014",
month = "6",
day = "25",
doi = "10.1016/j.cbi.2014.04.002",
language = "English",
volume = "217",
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journal = "Chemico-Biological Interactions",
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TY - JOUR

T1 - N-hydroxycinnamide derivatives of osthole inhibit cell migration and invasion by suppressing smad2 and akt pathways in human colorectal adenocarcinoma cells

AU - Liu, Ling Yu

AU - Huang, Wei Jan

AU - Ho, Feng Ming

AU - Lin, Ren-Jye

AU - Lin, Shyr Yi

AU - Suk, Fat Moon

AU - Liang, Yu Chih

PY - 2014/6/25

Y1 - 2014/6/25

N2 - 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 1 μM. 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.

AB - 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 1 μM. 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.

KW - Akt

KW - Invasion

KW - Migration

KW - Osthole

KW - Smad

KW - TGF-β

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U2 - 10.1016/j.cbi.2014.04.002

DO - 10.1016/j.cbi.2014.04.002

M3 - Article

VL - 217

SP - 1

EP - 8

JO - Chemico-Biological Interactions

JF - Chemico-Biological Interactions

SN - 0009-2797

ER -