S1P AND IL-1 COOPERATIVELY UP-REGULATE PAI-1 AND uPAR, IMPORTANT COMPONENTS FOR GLIOMA INVASION

BRYAN L, PAUGH BS, WILCZYNSKA KM, ALVAREZ SM, SINGH SK, KAPITONOV D, MILSTEIN S, SPIEGEL S, KORDULA T.

Tucson, Arizona

Congreso; FASEB Summer Research Conferences: Lysophospholipid Mediators in Health and Disease.; 2007

FASEB

Glioblastoma multiforme is extremely invasive, and thus evades the current standard treatments, While the precise mechanisms of invasion are not yet known, we hypothesized that they depend on the plasminogen activator system. The plasminogen activator system includes a serine protease, uPA (urokinase-type plasminogen activator), its inhibitor, PAI-1 (plasminogen activator inhibitor-1), and a cell surface receptor, uPAR (urokinase-type plasminogen activator receptor). Breast cancer patients with high levels of PAI-1 have a poor prognosis for survival, and it has been proposed that PAI-1 promotes cell detachment/migration by causing the internalization of the PAI-1/uPA/uPAR/integrin complex. This system is controlled by the pro-inflammatory cytokine IL-1 and the bioactive lipid sphingosine-1-phosphate (S1P). S1P has been implicated in cell proliferation, survival, migration and differentiation. Here we report that S1P can up-regulate the components of this system by itself, as well as cooperatively with IL-1 via divergent pathways. It is known that IL-1 activates sphingosine kinase-1 (SphK1), which produces S1P from sphingosine; however, we have established that IL-1 requires neither SphK1 nor the S1P receptors for the activation of PAI-1 and uPAR, but rather it acts on these components via another mechanism. In contrast, we discovered that S1P activation of PAI-1 and uPAR is dependent upon the S1P2 receptor. We also demonstrate that S1P and IL-1 increase the invasion of several glioblastoma cell lines.