Document Detail


Therapeutic targeting of the PDGF and TGF-beta-signaling pathways in hepatic stellate cells by PTK787/ZK22258.
MedLine Citation:
PMID:  19668241     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-08-10
Journal Detail:
Title:  Laboratory investigation; a journal of technical methods and pathology     Volume:  89     ISSN:  1530-0307     ISO Abbreviation:  Lab. Invest.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-09-28     Completed Date:  2009-10-27     Revised Date:  2013-06-21    
Medline Journal Info:
Nlm Unique ID:  0376617     Medline TA:  Lab Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1152-60     Citation Subset:  IM    
Affiliation:
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Movement / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Down-Regulation / drug effects
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / metabolism
Hepatic Stellate Cells / drug effects*,  metabolism
Liver Cirrhosis / drug therapy
Phthalazines / pharmacology*,  therapeutic use
Platelet-Derived Growth Factor / metabolism*
Protein Kinase Inhibitors / pharmacology*,  therapeutic use
Proto-Oncogene Proteins c-akt / metabolism
Pyridines / pharmacology*,  therapeutic use
RNA, Messenger / metabolism
Rats
Receptor, Platelet-Derived Growth Factor beta / metabolism
Receptors, Transforming Growth Factor beta / metabolism
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction / drug effects
Smad2 Protein / metabolism
Transforming Growth Factor beta1 / metabolism*
Vascular Endothelial Growth Factor A / metabolism
Vascular Endothelial Growth Factor Receptor-1 / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism
raf Kinases / metabolism
Grant Support
ID/Acronym/Agency:
DK56621/DK/NIDDK NIH HHS; R01 DK056621/DK/NIDDK NIH HHS; R01 DK056621-10/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Madh2 protein, rat; 0/Phthalazines; 0/Platelet-Derived Growth Factor; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/RNA, Messenger; 0/Receptors, Transforming Growth Factor beta; 0/Smad2 Protein; 0/Transforming Growth Factor beta1; 0/Vascular Endothelial Growth Factor A; 5DX9U76296/vatalanib; EC 2.7.10.1/Flt1 protein, rat; EC 2.7.10.1/Receptor, Platelet-Derived Growth Factor beta; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-1; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa; EC 2.7.11.1/raf Kinases; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

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