Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK

Toxicol Appl Pharmacol. 2005 Mar 1;203(2):124-31. doi: 10.1016/j.taap.2004.08.004.

Abstract

Since hepatocellular carcinoma remains a major challenging clinical problem in many parts of the world including Eastern Asia and Southern Africa, it is imperative to develop more effective chemopreventive and chemotherapy agents. Herein, we present an investigation regarding the anticancer potential of luteolin, a natural flavonoid, and the mechanism of its action in human hepatoma HepG2 cells. Using DNA fragmentation assay and nuclear staining assay, it showed that luteolin induced apoptosis of HepG2 cells. Luteolin induced the cytosolic release of cytochrome c and activated CPP32. We found that Bax and Bak translocated to mitochondria apparently, whereas Fas ligand (FasL) was unchanged after a treatment with luteolin for 3 h. In addition, it showed that c-Jun NH2-terminal kinase (JNK) was activated after the treatment of luteolin for 3-12 h. Further investigation showed that a specific JNK inhibitor, SP600125, reduced the activation of CPP 32, the mitochondrial translocation of Bax, as well as the cytosolic release of cytochrome c that induced by luteolin. Finally, the apoptosis induced by luteolin was suppressed by a pretreatment with SP600125 via evaluating annexin V-FITC binding assay. These data suggest that luteolin induced apoptosis via mechanisms involving mitochondria translocation of Bax/Bak and activation of JNK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Luteolin / pharmacology*
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Anticarcinogenic Agents
  • BAK1 protein, human
  • BAX protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Cytochromes c
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Luteolin