Journal
JOURNAL OF HEPATOLOGY
Volume 41, Issue 2, Pages 267-273Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2004.04.013
Keywords
SU5416; HGF/c-Met; invasiveness
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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 [H-3] thymidine. Invasiveness was assayed in Boyden Chambers with 8 mum 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. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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