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

TitleTherapeutic targeting of the PDGF and TGF-Β-signaling pathways in hepatic stellate cells by PTK787/ZK22258
Authors
Liu, YWen, XMLui, ELHFriedman, SLCui, WHo, NPSLi, LYe, TFan, STZhang, H
KeywordsAkt
HSC
PDGF
PTK787/ZK22258
TGF-Β1
Issue Date2009
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/
Citation
Laboratory Investigation, 2009, v. 89 n. 10, p. 1152-1160 How to Cite?
DOI: http://dx.doi.org/10.1038/labinvest.2009.77
AbstractStimulation 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. © 2009 USCAP, Inc All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/84555
ISSN
0023-6837
2022 Impact Factor: 5.0
2020 SCImago Journal Rankings: 1.542
PubMed Central ID
PMC2891536
ISI Accession Number ID
WOS:000270330200007
Funding AgencyGrant Number
Hong Kong Research Grants CouncilPolyU 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
NIHDK56621
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.

References
References in Scopus

 

DC FieldValueLanguage
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorWen, XMen_HK
dc.contributor.authorLui, ELHen_HK
dc.contributor.authorFriedman, SLen_HK
dc.contributor.authorCui, Wen_HK
dc.contributor.authorHo, NPSen_HK
dc.contributor.authorLi, Len_HK
dc.contributor.authorYe, Ten_HK
dc.contributor.authorFan, STen_HK
dc.contributor.authorZhang, Hen_HK
dc.date.accessioned2010-09-06T08:54:19Z-
dc.date.available2010-09-06T08:54:19Z-
dc.date.issued2009en_HK
dc.identifier.citationLaboratory Investigation, 2009, v. 89 n. 10, p. 1152-1160en_HK
dc.identifier.issn0023-6837en_HK
dc.identifier.urihttp://hdl.handle.net/10722/84555-
dc.description.abstractStimulation 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. © 2009 USCAP, Inc All rights reserved.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/en_HK
dc.relation.ispartofLaboratory Investigationen_HK
dc.subjectAkten_HK
dc.subjectHSCen_HK
dc.subjectPDGFen_HK
dc.subjectPTK787/ZK22258en_HK
dc.subjectTGF-Β1en_HK
dc.subject.meshHepatic Stellate Cells - drug effects - metabolism-
dc.subject.meshPhthalazines - pharmacology - therapeutic use-
dc.subject.meshPlatelet-Derived Growth Factor - metabolism-
dc.subject.meshProtein Kinase Inhibitors - pharmacology - therapeutic use-
dc.subject.meshTransforming Growth Factor beta1 - metabolism-
dc.titleTherapeutic targeting of the PDGF and TGF-Β-signaling pathways in hepatic stellate cells by PTK787/ZK22258en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0023-6837&volume=89&issue=10&spage=1152&epage=1160&date=2009&atitle=Therapeutic+targeting+of+the+PDGF+and+TGF-beta-signaling+pathways+in+hepatic+stellate+cells+by+PTK787/ZK22258en_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1038/labinvest.2009.77en_HK
dc.identifier.pmid19668241en_HK
dc.identifier.pmcidPMC2891536-
dc.identifier.scopuseid_2-s2.0-70349556686en_HK
dc.identifier.hkuros168443en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70349556686&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume89en_HK
dc.identifier.issue10en_HK
dc.identifier.spage1152en_HK
dc.identifier.epage1160en_HK
dc.identifier.isiWOS:000270330200007-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLiu, Y=14627533300en_HK
dc.identifier.scopusauthoridWen, XM=55197620600en_HK
dc.identifier.scopusauthoridLui, ELH=36865643400en_HK
dc.identifier.scopusauthoridFriedman, SL=35406698100en_HK
dc.identifier.scopusauthoridCui, W=35191650200en_HK
dc.identifier.scopusauthoridHo, NPS=36607999600en_HK
dc.identifier.scopusauthoridLi, L=26643123700en_HK
dc.identifier.scopusauthoridYe, T=7102429442en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK
dc.identifier.scopusauthoridZhang, H=7409192698en_HK
dc.identifier.citeulike5427181-
dc.identifier.issnl0023-6837-

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