SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells

Si Y. Wang, Bing Chen, Yi Q. Zhan, Wang X. Xu, Chang Y. Li, Ri F. Yang, Hong Zheng, Pei B. Yue, Steven H. Larsen, Hui (Herb) Sun, Xiaoming Yang

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Background/Aims SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor. Methods Cell proliferation was determined by incorporation of [3H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 μm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting. Results We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met. Conclusions Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.

Original languageEnglish (US)
Pages (from-to)267-273
Number of pages7
JournalJournal of Hepatology
Volume41
Issue number2
DOIs
StatePublished - Aug 2004
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-met
Hepatocyte Growth Factor
Hep G2 Cells
Hepatocellular Carcinoma
Phosphorylation
Proto-Oncogene Proteins c-kit
Platelet-Derived Growth Factor Receptors
Vascular Endothelial Growth Factor Receptor
Receptor Protein-Tyrosine Kinases
Growth
Thymidine
Tyrosine
Hepatocytes
Neoplasms
Fibroblasts
Western Blotting
Cell Proliferation
Semaxinib
Neoplasm Metastasis
Cell Line

Keywords

  • c-Met, hepatocyte growth factor receptor
  • ERK, extracellular signal-regulated kinase
  • HGF/c-Met
  • HGF/SF, hepatocyte growth factor/scatter factor
  • Invasiveness
  • MDCK, Madin-Darby canine kidney cells
  • SU5416
  • VEGF, vascular endothelial growth factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells. / Wang, Si Y.; Chen, Bing; Zhan, Yi Q.; Xu, Wang X.; Li, Chang Y.; Yang, Ri F.; Zheng, Hong; Yue, Pei B.; Larsen, Steven H.; Sun, Hui (Herb); Yang, Xiaoming.

In: Journal of Hepatology, Vol. 41, No. 2, 08.2004, p. 267-273.

Research output: Contribution to journalArticle

Wang, Si Y. ; Chen, Bing ; Zhan, Yi Q. ; Xu, Wang X. ; Li, Chang Y. ; Yang, Ri F. ; Zheng, Hong ; Yue, Pei B. ; Larsen, Steven H. ; Sun, Hui (Herb) ; Yang, Xiaoming. / SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells. In: Journal of Hepatology. 2004 ; Vol. 41, No. 2. pp. 267-273.
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abstract = "Background/Aims SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor. Methods Cell proliferation was determined by incorporation of [3H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 μm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting. Results We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met. Conclusions Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.",
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T1 - SU5416 is a potent inhibitor of hepatocyte growth factor receptor (c-Met) and blocks HGF-induced invasiveness of human HepG2 hepatoma cells

AU - Wang, Si Y.

AU - Chen, Bing

AU - Zhan, Yi Q.

AU - Xu, Wang X.

AU - Li, Chang Y.

AU - Yang, Ri F.

AU - Zheng, Hong

AU - Yue, Pei B.

AU - Larsen, Steven H.

AU - Sun, Hui (Herb)

AU - Yang, Xiaoming

PY - 2004/8

Y1 - 2004/8

N2 - Background/Aims SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor. Methods Cell proliferation was determined by incorporation of [3H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 μm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting. Results We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met. Conclusions Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.

AB - Background/Aims SU5416 is a potent inhibitor of receptor tyrosine kinases, including those of the vascular endothelial growth factor receptor, stem cell factor receptor, and platelet-derived growth factor receptor. Because of the overwhelming evidence favoring the role of aberrant hepatocyte growth factor (HGF)/Met signaling in the pathogenesis of various human cancers, various inhibitor strategies have been employed to therapeutically target this receptor. Methods Cell proliferation was determined by incorporation of [3H] thymidine. Invasiveness was assayed in Boyden Chambers with 8 μm Matrigel coated filters. Phosphorylation of ERK1/2, Akt by HGF stimulation was detected by Western blotting. Results We found that SU5416 inhibited motility scattering and the invasive activity of a hepatocellular carcinoma cell line HepG2 in vitro and growth in primary cultured hepatocytes induced by HGF. Consequently, tyrosine autophosphorylation of the c-met induced by HGF was inhibited in these cells by SU5416 in a dose-dependent manner. Furthermore, ERK1/2 and Akt phosphorylation, the signaling events down-stream of c-met activation were reduced. Moreover, SU5416 caused reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, Tpr-Met. Conclusions Inhibition of various solid tumors growth and metastasis by SU5416 may be partially attributed to blocking activation of the hepatocyte growth factor receptor.

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KW - HGF/c-Met

KW - HGF/SF, hepatocyte growth factor/scatter factor

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KW - SU5416

KW - VEGF, vascular endothelial growth factor

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