Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways

Chem Biol Interact. 2006 Mar 25;160(2):123-33. doi: 10.1016/j.cbi.2006.01.002. Epub 2006 Feb 3.


Hepatocyte growth factor (HGF), also known as scatter factor (SF), and its receptor, the c-Met tyrosine kinase, play roles in cancer invasion and metastasis in a wide variety of tumor cells. Clinical observations suggest that HGF can promote metastasis of hepatoma cells while stimulating tumor invasiveness. We use HGF as an invasive inducer of human hepatoma HepG2 cells to investigate the effect of flavonoids on anti-invasion. In our preliminary study, we investigated the effect of flavonoids including luteolin, quercetin, baicalein, genistein, taxifolin and catechin on HGF-mediated migration and invasion of HepG2 cells. We found that luteolin presented the most potent potential on anti-migration and anti-invasion by Boyden chamber assay. Furthermore, luteolin inhibited HGF-induced cell scattering and cytoskeleton change such as filopodia and lamellipodia was determined by both phase-contrast and fluorescence microscopy studies. In addition, Western blotting and immunoprecipitation were performed to confirm luteolin suppressed the phosphorylation of c-Met, the membrane receptor of HGF, as well as ERK1/2 and Akt, but not JNK1/2, which is activated by HGF. Our investigation demonstrated that luteolin similar to PD98059, which acts as a specific inhibitor of MEK, an up stream kinase regulating ERK1/2, and wortmannin, a PI3K inhibitor, inhibited the invasiveness induced by HGF. In conclusion, the luteolin inhibited HGF-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Drug Interactions
  • Hepatocyte Growth Factor / pharmacology*
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Hepatocytes / pathology
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / pathology
  • Luteolin / pharmacology*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Invasiveness / prevention & control
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism


  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases
  • Luteolin