Targeting SphK1 as a new strategy against cancer.

Sphingolipid metabolites have emerged as critical players in a number of fundamental biological processes. Among them, sphingosine-1-phosphate (S1P) promotes cell survival and proliferation, in contrast to ceramide and sphingosine, which induce cell growth arrest and apoptosis. These sphingolipids with opposing functions are interconvertible inside cells, suggesting that a finely tuned balance between them can determine cell fate. Sphingosine kinases (SphKs), which catalyze the phosphorylation of sphingosine to S1P, are critical regulators of this balance. Of the two identified SphKs, sphingosine kinase type 1 (SphK1) has been shown to regulate various processes important for cancer progression and will be the focus of this review, since much less is known of biological functions of SphK2, especially in cancer. SphK1 is overexpressed in various types of cancers and upregulation of SphK1 has been associated with tumor angiogenesis and resistance to radiation and chemotherapy. Many growth factors, through their tyrosine kinase receptors (RTKs), stimulate SphK1 leading to a rapid increase in S1P. This S1P in turn can activate S1P receptors and their downstream signaling. Conversely, activation of S1P receptors can induce transactivation of various RTKs. Thus, SphK1 may play important roles in S1P receptor RTK amplification loops. Here we review the role of SphK1 in tumorigenesis, hormonal therapy, chemotherapy resistance, and as a prognostic marker. We will also review studies on the effects of SphK inhibitors in cells in vitro and in animals in vivo and in some clinical trials and highlight the potential of SphK1 as a new target for cancer therapeutics.