Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis

Mol Pharmacol. 2000 Apr;57(4):792-6. doi: 10.1124/mol.57.4.792.


Previous work has demonstrated that down-regulation of ceramide production after selection of cells with N-oleoylethanolamine (OE), an inhibitor of ceramidase, results in resistance to DNA damage-induced apoptosis. We report here that acute exposure of WEHI-231 cells (murine B-cell lymphoma) to OE activates neutral sphingomyelinase, induces ceramide production and increases intracellular reactive oxygen species. OE exposure also induces mitochondrial permeability, cytochrome c release, and apoptosis. Cells selected for resistance to OE exhibit little if any change in reactive oxygen species and cytochrome c release when exposed either to OE or to toxic doses of ceramide. Importantly, the OE resistant cells are also resistant to ionizing radiation-induced cytochrome c release and apoptosis. These findings demonstrate that down-regulation of neutral sphingomyelinase activity is associated with decreased DNA-damage-induced apoptosis. In addition, the data suggests that agents that modify extranuclear targets responsible for ceramide production select for cells resistant to ionizing radiation-induced apoptosis through alterations in mitochondrial function.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Ceramides / metabolism*
  • Cytochrome c Group / metabolism*
  • Down-Regulation
  • Endocannabinoids
  • Enzyme Activation / radiation effects
  • Enzyme Inhibitors / pharmacology
  • Ethanolamines / pharmacology
  • Mice
  • Mitochondria / metabolism
  • Oleic Acids
  • Permeability
  • Radiation, Ionizing
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / metabolism
  • Sphingomyelin Phosphodiesterase / radiation effects
  • Tumor Cells, Cultured


  • Ceramides
  • Cytochrome c Group
  • Endocannabinoids
  • Enzyme Inhibitors
  • Ethanolamines
  • Oleic Acids
  • N-oleoylethanolamine
  • Sphingomyelin Phosphodiesterase