Therapeutic Targeting of the PDGF and TGF-beta-signaling Pathways in Hepatic Stellate Cells by PTK787/ZK22258

Overview

Journal Lab Invest

Specialty Pathology

Date 2009 Aug 12

PMID 19668241

Citations 23

Authors

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

Affiliations

Soon will be listed here.

Abstract

Stimulation of hepatic stellate cells (HSCs) by platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) 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-beta1-induced expression of VEGF and VEGFR1. Furthermore, PTK/ZK downregulates TGF-beta receptor expression, which is associated with reduced Akt, ERK and p38MAPK phosphorylation. Furthermore, PDGF-induced TGF-beta1 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.

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