Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway

Hepatology. 2008 Jun;47(6):1964-73. doi: 10.1002/hep.22240.


Melittin, a water-soluble toxic peptide derived from bee venom of Apis mellifera was reported to have inhibitory effects on hepatocellular carcinoma (HCC). However, its role in antimetastasis and the underlying mechanism remains elusive. By utilizing both HCC cell lines and an animal model based assay system, we found that Rac1, which has been shown to be involved in cancer cell metastasis, is highly expressed in aggressive HCC cell lines and its activity correlated with cell motility and cytoskeleton polymerization. In addition, Rac1-dependent activity and metastatic potential of aggressive HCC cells are remarkably high in both cellular and nude mouse models. We provide evidence here that melittin inhibits the viability and motility of HCC cells in vitro, which correlates with its suppression of Rac1-dependent activity, cell motility, and microfilament depolymerization. Furthermore, melittin suppresses both HCC metastasis and Rac1-dependent activity in nude mouse models. The specificity of the effect of melittin on Rac1 was confirmed in HCC cells both in vitro and in vivo.

Conclusion: Melittin inhibits tumor cell metastasis by reducing cell motility and migration via the suppression of Rac1-dependent pathway, suggesting that melittin is a potential therapeutic agent for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control*
  • MAP Kinase Kinase 4 / metabolism
  • Melitten / pharmacology*
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / prevention & control
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Xenograft Model Antitumor Assays
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • RAC1 protein, human
  • Melitten
  • MAP Kinase Kinase 4
  • rac1 GTP-Binding Protein