Abstract
We have shown that liver myofibroblasts stimulate in vitro invasion of hepatocellular carcinoma cell lines through a hepatocyte growth factor/urokinase-dependent mechanism. Resveratrol, a grapevine-derived polyphenol, has been shown to inhibit cellular events associated with tumor initiation, promotion and progression. The aim of this study was to evaluate the effects of trans-resveratrol on invasion of the human hepatoma cell line HepG2. Cell invasion was assessed using a Boyden chamber assay. Activation of the HGF signal transduction pathways was evaluated by Western blot with phospho-specific antibodies. Urokinase expression was measured by RT-PCR and zymography. Trans-resveratrol decreased hepatocyte growth factor-induced cell scattering and invasion. It also decreased cell proliferation without evidence for cytotoxicity or apoptosis. Trans-resveratrol did not decrease the level of the hepatocyte growth factor receptor c-met and did not impede the hepatocyte growth factor-induced increase in c-met precursor synthesis. Moreover, trans-resveratrol did not decrease hepatocyte growth factor-induced c-met autophosphorylation, or Akt-1 or extracellular-regulated kinases-1 and -2 activation. Finally, it did not decrease urokinase expression and did not block the catalytic activity of urokinase. In conclusion, our results demonstrate that trans-resveratrol decreases hepatocyte growth factor-induced HepG2 cell invasion by an as yet unidentified post-receptor mechanism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Cell Division
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Cell Survival
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Flavonoids*
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Hepatocyte Growth Factor / antagonists & inhibitors*
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Hepatocyte Growth Factor / pharmacology
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Humans
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Neoplasm Invasiveness
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Phenols / pharmacology*
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Phosphorylation
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Poly(ADP-ribose) Polymerases / metabolism
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Polymers / pharmacology*
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Polyphenols
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-met / metabolism
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Proto-Oncogene Proteins*
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RNA, Messenger / biosynthesis
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Receptors, Cell Surface / metabolism
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Receptors, Urokinase Plasminogen Activator
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Resveratrol
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Stilbenes / pharmacology*
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Tetrazolium Salts
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Thiazoles
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Tumor Cells, Cultured / drug effects
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Urokinase-Type Plasminogen Activator / biosynthesis
Substances
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Antineoplastic Agents, Phytogenic
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Flavonoids
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PLAUR protein, human
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Phenols
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Polymers
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Polyphenols
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Cell Surface
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Receptors, Urokinase Plasminogen Activator
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Stilbenes
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Tetrazolium Salts
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Thiazoles
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Hepatocyte Growth Factor
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Poly(ADP-ribose) Polymerases
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Proto-Oncogene Proteins c-met
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase Kinases
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Urokinase-Type Plasminogen Activator
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thiazolyl blue
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Resveratrol