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 B. Sun, Xiaoming Yang

Research output: Contribution to journalArticle

49 Scopus citations

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
Publication statusPublished - Aug 1 2004
Externally publishedYes

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Keywords

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

ASJC Scopus subject areas

  • Hepatology

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