Activation of c-Jun-N-terminal kinase is required for apoptosis triggered by glutathione disulfide in neuroblastoma cells

Free Radic Biol Med. 2005 Aug 1;39(3):345-54. doi: 10.1016/j.freeradbiomed.2005.03.022. Epub 2005 Apr 7.


Changes in intracellular redox status are crucial events that trigger downstream proliferation or death responses through activation of specific signaling pathways. Moreover, cell responses to oxidative challenge may depend on the pattern of redox-sensitive molecular factors. The stress-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 MAP kinase (p38MAPK) are implicated in different forms of apoptotic neuronal cell death. Here, we investigated the effects, on neuroblastoma cells, of the prooxidant molecule GSSG, which we previously demonstrated to be an efficient proapoptotic compound able to activate the p38MAPK death pathway in promonocytic cells. We found that neuroblastoma cells are not prone to GSSG-induced apoptosis, although the treatment slightly induced growth arrest through the accumulation of p53 and its downstream target gene, p21. However, GSSG treatment became cytotoxic when cells were previously depleted of intracellular GSH content. Under this condition, apoptosis was triggered by an increased production of superoxide that led to a specific activation of the JNK-dependent pathway. The involvement of superoxide and JNK was demonstrated by cell death inhibition in experiments carried out in the presence of Cu,Zn superoxide dismutase or with specific inhibitors of JNK activity. Our data give support to the studies that indicate preferential requirements for the involvement of stress-activated kinases in apoptotic neuronal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Enzyme Activation / physiology*
  • Glutathione / drug effects
  • Glutathione / metabolism
  • Glutathione Disulfide / metabolism
  • Glutathione Disulfide / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Neuroblastoma / enzymology*
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Superoxides
  • Superoxide Dismutase
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Glutathione
  • Glutathione Disulfide