Over 100,000 people develop gliomas in the United States annually. These primary tumors, which are resistant to surgery and radiotherapy, are characterized by an invasive phenotype that results in the diffuse infiltration of the tumor cells as deeply as several centimeters into the brain. Invasion of the glioma cells, in part, depends on the deregulation of the proteolytic balance, which allows them to degrade the extracellular matrix, migrate, and invade healthy tissue. This deregulation involves the plasminogen activator (PA) system and metalloproteinases/tissue inhibitors of metalloproteinases. The expression of the PA system is tightly controlled by cytokines and growth factors, including IL-1 and EGF, in glioma cells. Surprisingly, we have recently discovered that sphingosine kinase 1 (SphK1) is an important mediator of EGF signaling, which activates the expression of the PA system in gliomas via a novel pathway composed of c-Src, PKCdelta, and SphK1. We also found that this system is regulated by sphingosine-1-phosphate (S1P), a sphingolipid metabolite produced in cells by the phosphorylation of sphingosine catalyzed by two SphK: isozymes (SphK1 and 2). S1P regulates a wide variety of cellular processes that are critical for the growth and invasion of glioma cells, including cytoskeletal rearrangements and cell movement, angiogenesis and vascular maturation, inflammation, and lymphocyte trafficking. Moreover, S1P stimulates the invasiveness of human glioblastoma cells, and elevated SphK1 expression correlates with the poor survival of patients with glioblastoma multiforme. We hypothesize that the cytokine-, growth factor-mediated stimulation of SphKs expression leads to the production of S1P, which in turn activates the proliferation, mobility, and invasion of glioma cells. Therefore, our specific aims are as follows: ? Specific Aim 1. To analyze the effects of the over-expression1 of both SphK1 and SphK2 on the proliferation, mobility, invasion, and the expression of the PA system in gliomas in vitro and in vivo. ? Specific Aim 2. To analyze the effects of the knock-down of both SphK1 and SphK2 on the proliferation, mobility, invasion, and the expression of the PA system in gliomas in vitro and in vivo. ? ?
| Singh, Sandeep K; Wilczynska, Katarzyna M; Grzybowski, Adrian et al. (2011) The unique transcriptional activation domain of nuclear factor-I-X3 is critical to specifically induce marker gene expression in astrocytes. J Biol Chem 286:7315-26 |
| Wilczynska, Katarzyna M; Singh, Sandeep K; Adams, Bret et al. (2009) Nuclear factor I isoforms regulate gene expression during the differentiation of human neural progenitors to astrocytes. Stem Cells 27:1173-81 |
| Paugh, Barbara S; Bryan, Lauren; Paugh, Steven W et al. (2009) Interleukin-1 regulates the expression of sphingosine kinase 1 in glioblastoma cells. J Biol Chem 284:3408-17 |
