Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines

J Neuropathol Exp Neurol. 2005 Aug;64(8):695-705. doi: 10.1097/01.jnen.0000175329.59092.2c.


Sphingosine-1-phosphate is a bioactive lipid that is mitogenic for human glioma cell lines by signaling through its G protein-coupled receptors. We investigated the role of sphingosine-1-phosphate receptors and the enzymes that form sphingosine-1-phosphate, sphingosine kinase (SphK)-1, and -2 in human astrocytomas. Astrocytomas of various histologic grades expressed three types of sphingosine-1-phosphate receptors, S1P1, S1P2, and S1P3; however, no significant correlation with histologic grade or patient survival was detected. Expression of SphK1, but not SphK2, in human astrocytoma grade 4 (glioblastoma multiforme) tissue correlated with short patient survival. Patients whose tumors had low SphK1 expression survived a median 357 days, whereas those with high levels of SphK1 survived a median 102 days. Decreasing SphK1 expression using RNA interference or pharmacologic inhibition of SphK significantly decreased the rate of proliferation of U-1242 MG and U-87 MG glioblastoma cell lines. Surprisingly, RNA interference to knockdown SphK2 expression inhibited glioblastoma cell proliferation more potently than did SphK1 knockdown. SphK knockdown also prevented cells from exiting G1 phase of the cell cycle and marginally increased apoptosis. Thus, SphK isoforms may be major contributors to growth of glioblastoma cells in vitro and to aggressive behavior of glioblastoma multiforme.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Northern / methods
  • Blotting, Western / methods
  • Cell Count / methods
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Enlargement / drug effects
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Glioblastoma / metabolism*
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Glioblastoma / physiopathology
  • Humans
  • Middle Aged
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Time Factors


  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Lysosphingolipid
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase