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

doi:10.1038/labinvest.2009.77

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	1152-1160
Number of pages	9
Journal	Laboratory Investigation
Volume	89
Issue number	10
DOIs	https://doi.org/10.1038/labinvest.2009.77
State	Published - Oct 2009

Keywords

Akt
HSC
PDGF
PTK787/ZK22258
TGF-Β1

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10.1038/labinvest.2009.77

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@article{c86f82eccecf46569174b712dbbc64ef,

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

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.",

keywords = "Akt, HSC, PDGF, PTK787/ZK22258, TGF-Β1",

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

note = "Funding Information: The authors thank Professor Mien-Chie Hung (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.), Dr Jeremy Hughes (MRC Center for Inflammation Research, University of Edinburgh, UK) and Dr Nai-Sum Wong (Department of Biochemistry, The University of Hong Kong) for their valuable advice and comments, as well as Xueming Qian for technical assistance. We acknowledge financial support from the Hong Kong Research Grants Council (Projects: PolyU 5407/06M; PolyU 5638/07M); Shenzhen Bureau of Science, Technology and Information (Shenzhen Key Laboratory Advancement Scheme); Small Project Funding Programme of the University of Hong Kong; and NIH Grant DK56621.",

year = "2009",

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doi = "10.1038/labinvest.2009.77",

language = "English",

volume = "89",

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journal = "Laboratory Investigation",

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T1 - Therapeutic targeting of the PDGF and TGF-Β-signaling pathways in hepatic stellate cells by PTK787/ZK22258

AU - Liu, Yuqing

AU - Wen, Xiao Ming

AU - Lui, Eric Lik Hang

AU - Friedman, Scott L.

AU - Cui, Wei

AU - Ho, Nancy Pei Shan

AU - Li, Lei

AU - Ye, Tao

AU - Fan, Sheung Tat

AU - Zhang, Hui

N1 - Funding Information: The authors thank Professor Mien-Chie Hung (Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.), Dr Jeremy Hughes (MRC Center for Inflammation Research, University of Edinburgh, UK) and Dr Nai-Sum Wong (Department of Biochemistry, The University of Hong Kong) for their valuable advice and comments, as well as Xueming Qian for technical assistance. We acknowledge financial support from the Hong Kong Research Grants Council (Projects: PolyU 5407/06M; PolyU 5638/07M); Shenzhen Bureau of Science, Technology and Information (Shenzhen Key Laboratory Advancement Scheme); Small Project Funding Programme of the University of Hong Kong; and NIH Grant DK56621.

PY - 2009/10

Y1 - 2009/10

N2 - 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.

AB - 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.

KW - Akt

KW - HSC

KW - PDGF

KW - PTK787/ZK22258

KW - TGF-Β1

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U2 - 10.1038/labinvest.2009.77

DO - 10.1038/labinvest.2009.77

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AN - SCOPUS:70349556686

SN - 0023-6837

VL - 89

SP - 1152

EP - 1160

JO - Laboratory Investigation

JF - Laboratory Investigation

IS - 10

ER -

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

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Keywords

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