INTERLEUKIN-1 REGULATES EXPRESSION OF SPHINGOSINE KINASE 1 VIA ACTIVATION OF JNK/C-JUN PATHWAY IN GLIOBLASTOMA CELLS

PAUGH BS, PAUGH SW, BRYAN LE, KAPITONOV D, WILCZYNSKA KM, ALVAREZ SM, SINGH SK, ROKITA H, MILSTEIN S, SPIEGEL S, KORDULA T.

Richmond, Virginia

Jornada; Integrative Cellular and Molecular Signaling (ICAMS) Research Retreat; 2007

Virginia Commonwealth University

Chronic inflammation and proinflammatory cytokines have recently been implicated in the development and progression of various types of cancer, including glioblastoma multiforme. In the brain, neuroinflammatory cytokines such as Interleukin 1 (IL-1)  affect growth and differentiation of both normal and malignant glial cells. Recently, elevated levels of sphingosine kinase type 1 (SphK1) were shown to strongly correlate with shorter survival prognosis of patients with glioblastoma multiforme. SphK1 is a lipid kinase that produces the pro-growth anti-apoptotic sphingosine 1-phosphate (S1P), which can induce invasion of glioma cells. Here, we show that IL-1 upregulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines; however, it does not affect SphK2 expression. Furthermore, SphK1a and SphK1c are the major isoforms expressed in these cells and both isoforms are similarly regulated by IL-1. IL-1 activates multiple signaling molecules in glioblastoma cells, however, the IL-1- induced SphK1 upregulation can be blocked by the inhibition of JNK (by SP600125 and JNK peptide inhibitor I), the overexpression of dominant negative c-jun (TAM 67), and the downregulation of c-jun expression by siRNA. Activation of SphK1 expression by IL-1 occurs on the level of transcription and is mediated by several AP1/ATF/CREB binding and this pathway may be important in regulating survival of glioblastoma cells.