Sphingosine-1-phosphate and interleukin-1 independently regulate plasminogen activator inhibitor-1 and urokinase-type plasminogen activator receptor expression in glioblastoma cells: implications for invasiveness

Mol Cancer Res. 2008 Sep;6(9):1469-77. doi: 10.1158/1541-7786.MCR-08-0082.


Glioblastoma multiforme is an invasive primary brain tumor, which evades the current standard treatments. The invasion of glioblastoma cells into healthy brain tissue partly depends on the proteolytic and nonproteolytic activities of the plasminogen activator system proteins, including the urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and a receptor for uPA (uPAR). Here we show that sphingosine-1-phosphate (S1P) and the inflammatory mediator interleukin-1 (IL-1) increase the mRNA and protein expression of PAI-1 and uPAR and enhance the invasion of U373 glioblastoma cells. Although IL-1 enhanced the expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, down-regulation of SphK1 had no effect on the IL-1-induced uPAR or PAI-1 mRNA expression, suggesting that these actions of IL-1 are independent of S1P production. Indeed, the S1P-induced mRNA expression of uPAR and PAI-1 was blocked by the S1P(2) receptor antagonist JTE013 and by the down-regulation of S1P(2) using siRNA. Accordingly, the inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and Rho-kinase, two downstream signaling cascades activated by S1P(2), blocked the activation of PAI-1 and uPAR mRNA expression by S1P. More importantly, the attachment of glioblastoma cells was inhibited by the addition of exogenous PAI-1 or siRNA to uPAR, whereas the invasion of glioblastoma cells induced by S1P or IL-1 correlated with their ability to enhance the expression of PAI-1 and uPAR. Collectively, these results indicate that S1P and IL-1 activate distinct pathways leading to the mRNA and protein expression of PAI-1 and uPAR, which are important for glioblastoma invasiveness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Northern
  • Blotting, Western
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Adhesion / physiology
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Interleukin-1 / pharmacology*
  • Lysophospholipids / pharmacology*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasm Invasiveness
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Plasminogen Activator Inhibitor 1 / chemistry
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Urokinase Plasminogen Activator
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Tumor Cells, Cultured
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism


  • Interleukin-1
  • Lysophospholipids
  • PLAUR protein, human
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • SERPINE1 protein, human
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Mitogen-Activated Protein Kinases
  • Urokinase-Type Plasminogen Activator
  • Sphingosine