Regulation of human sphingosine kinase expression in normal and cancer cells

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We have previously shown that sphingosine kinase I (SK1) is frequently over-expressed in various human tumor cell types. In addition, an increasing number of studies have demonstrated that SK1 stimulated cell proliferation and could function as an oncogene. To date, however, little is known about the mechanism by which SK1 gene and/or protein expression is regulated in normal and cancer cells. To address this, we have performed a series of experiments to investigate the effect of platelet-derived growth factor (PDGF) or tumor necrosis factor (TNF-α) on SK1 expression in several human normal and tumor cell types. When human coronary artery smooth muscle cells and hepatoblastoma cell line Hep G2 were treated with PDGF and TNF-α, respectively, we observed a significant increase in SK1 gene and protein expression in a time-dependent manner. Pretreatment of cells with inhibitors for protein kinase C (PKC), Akt, and MEK potently inhibited SK1 gene/protein expression whereas SK1 inhibitor pretreatment showed no significant inhibitory effect, suggesting a PKC-dependent SK gene/protein expression. Interestingly, SK gene/protein expression in human mammary carcinoma MCF-7 and MDA-MB 231 cell lines was significantly higher than normal human mammary epithelial MCF-10A cells indicating that the regulation of SK expression might be altered in cancer cells. These dynamic regulatory mechanisms of SK expression will be discussed.