Targeting Sphingosine Kinase in Cancer Cells; Molecular Regulation of Sphingosine Kinase Signaling Pathways in Oncogenesis

The primary research interest of our laboratory is focused on the identification of mechanisms involved in the oncogenic role of sphingosine kinase (SK). In cancer cells, dysregulation of cell growth and/or apoptosis is closely linked to the sphingolipid metabolites, ceramide and sphingosine-l-phosphate (S-1-P). Ceramide induces cell growth arrest and apoptosis whereas S-1-P, a further metabolite of ceramide, promotes cell growth and/or protects from apoptosis. Ample evidence indicates that S-1-P, formed by activation of SK, can serve as an intracellular second messenger which modulates signaling pathways critical for cancer cell growth and survival.
In fact, S-1-P antagonizes apoptosis mediated by ceramide, a stress-induced sphingolipid metabolite, suggesting that the intracellular ratio of these two sphingolipid metabolites and consequent regulation of opposing signaling pathways, are important factors that determine the fate of cancer cells. It is our hypothesis that SK, which catalyzes formation of S-1-P, plays a pivotal role in regulation of cancer cell proliferation and/or survival. Currently, we are examining the critical role of SK in cancer cell growth. Additionally, we are characterizing the potential interactions of SK, and its product S-1-P, with signaling pathways known to be involved in mitogenesis and/or oncogenesis. Elucidation of the mechanism involved in the oncogenic role of SK will enhance our understanding of how these regulated pathways of sphingolipid metabolism modulate cancer cell growth and survival.