Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy

Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19569-74. doi: 10.1073/pnas.1115484108. Epub 2011 Nov 21.


The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Bridged-Ring Compounds / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic*
  • Cells
  • Gene Expression Regulation, Enzymologic
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Immunoblotting
  • Jurkat Cells
  • Membrane Microdomains / drug effects
  • Membrane Microdomains / metabolism
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Norbornanes
  • Oleic Acids / pharmacology*
  • Phosphodiesterase Inhibitors / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingomyelins / metabolism*
  • Thiocarbamates
  • Thiones / pharmacology
  • Transferases (Other Substituted Phosphate Groups) / antagonists & inhibitors
  • Transferases (Other Substituted Phosphate Groups) / genetics
  • Transferases (Other Substituted Phosphate Groups) / metabolism*
  • fas Receptor / metabolism
  • ras Proteins / metabolism


  • 2-hydroxyoleic acid
  • Bridged-Ring Compounds
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Norbornanes
  • Oleic Acids
  • Phosphodiesterase Inhibitors
  • Sphingomyelins
  • Thiocarbamates
  • Thiones
  • fas Receptor
  • tricyclodecane-9-yl-xanthogenate
  • SGMS1 protein, human
  • Transferases (Other Substituted Phosphate Groups)
  • phosphatidylcholine-ceramide phosphocholine transferase
  • ras Proteins