Therapeutic targeting of the PDGF and TGF-Β-signaling pathways in hepatic stellate cells by PTK787/ZK22258

Yuqing Liu, Xiao Ming Wen, Eric Lik Hang Lui, Scott L. Friedman, Wei Cui, Nancy Pei Shan Ho, Lei Li, Tao Ye, Sheung Tat Fan, Hui Zhang

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Stimulation of hepatic stellate cells (HSCs) by platelet-derived growth factor (PDGF) and transforming growth factor-Β1 (TGF-Β1) is an essential pathway of proliferation and fibrogenesis, respectively, in liver fibrosis. We provide evidence that PTK787/ZK222584 (PTK/ZK), a potent tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor (VEGFR), significantly inhibits PDGF receptor expression, as well as PDGF-simulated HSC proliferation, migration and phosphorylation of ERK1/2, Akt and p70S6 kinase. Interestingly, PTK/ZK also antagonizes the TGF-Β1-induced expression of VEGF and VEGFR1. Furthermore, PTK/ZK downregulates TGF-Β receptor expression, which is associated with reduced Akt, ERK and p38MAPK phosphorylation. Furthermore, PDGF-induced TGF-Β1 expression is inhibited by PTK/ZK. These findings provide evidence that PTK/ZK targets multiple essential pathways of stellate cell activation that provoke proliferation and fibrogenesis. Our study underscores the potential use of PTK/ZK as an antifibrotic drug in chronic liver disease.

Original languageEnglish
Pages (from-to)1152-1160
Number of pages9
JournalLaboratory Investigation
Volume89
Issue number10
DOIs
StatePublished - Oct 2009

Keywords

  • Akt
  • HSC
  • PDGF
  • PTK787/ZK22258
  • TGF-Β1

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