Trans-resveratrol, a grapevine-derived polyphenol, blocks hepatocyte growth factor-induced invasion of hepatocellular carcinoma cells

We have shown that liver myofibroblasts stimulate in vitro invasion of hepa tocellular carcinoma cell lines through a hepatocyte growth facror/urokinas e-dependent mechanism. Resveratrol, a grapevine-derived polyphenol, has bee n shown to inhibit cellular events associated with tumor initiation, promot ion and progression. The aim of this study was to evaluate the effects of t rans-resveratrol on invasion of the human hepatoma cell line HepG2. Cell in vasion was assessed using a Boyden chamber assay. Activation of the HGF sig nal transduction pathways was evaluated by Western blot with phospho-specif ic antibodies. Urokinase expression was measured by RT-PCR and zymography. Trans-resveratrol decreased hepatocyte growth factor-induced cell scatterin g and invasion. It also decreased cell proliferation without evidence for c ytotoxicity or apoptosis. Trans-resveratrol did not decrease the level of t he hepatocyte growth factor receptor c-met and did not impede the hepatocyt e growth factor-induced increase in c-met precursor synthesis. Moreover, tr ans-resveratrol did not decrease hepatocyte growth factor-induced c-met aut ophosphorylation, or Akt-1 or extracellular-regulated kinases-l and -2 acti vation. Finally, it did not decrease urokinase expression and did not block the catalytic activity of urokinase. In conclusion, our results demonstrat e that trans-resveratrol decreases hepatocyte growth factor-induced HepG2 c ell invasion by an as yet unidentified post-receptor mechanism.