Redox stress regulates cell proliferation and apoptosis of human hepatoma through Akt protein phosphorylation

FEBS Lett. 2003 May 8;542(1-3):60-4. doi: 10.1016/s0014-5793(03)00338-7.


Employing a spin trapping agent combined with electron spin resonance spectroscopy, we were able to capture reactive oxygen species (ROS) in living hepatoma cells and first found that the trapped ROS was superoxide anion (O(2)(z.rad;-)). O(2)(z.rad;-) suppressed by treatment with diphenylene iodonium, a flavoprotein inhibitor, was generated by the flavoprotein-containing NADPH-oxidase complex. Applying endogenous/exogenous pro-oxidant or antioxidant causes different redox states in hepatoma cells. Akt activity and cell growth were significantly stimulated by treating hepatoma cells with low concentration of ROS, which could be abolished by adding antioxidants. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (0.15 microM) inhibited Akt phosphorylation induced by ROS. Our results indicate that hepatoma cell growth is ROS-dependent, and fluctuation of the intracellular redox state may regulate hepatoma cell growth through Akt phosphorylation and the PI3K/Akt pathway, resulting in a broad array of responses from cellular proliferation to apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Apoptosis*
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Division / drug effects
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Oxidation-Reduction
  • Oxidative Stress*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Reactive Oxygen Species / metabolism
  • Spin Trapping
  • Superoxides / analysis
  • Tumor Cells, Cultured


  • Antioxidants
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Superoxides
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt