S1P metabolism in cancer and other pathological conditions

Abstract

Nearly two decades ago, the sphingolipid metabolite sphingosine 1-phosphate was discovered to function as a lipid mediator and regulator of cell proliferation. Since that time, sphingosine 1-phosphate has been shown to mediate a diverse array of fundamental biological processes including cell proliferation, migration, invasion, angiogenesis, vascular maturation and lymphocyte trafficking. Sphingosine 1-phosphate acts primarily via signaling through five ubiquitously expressed G protein-coupled receptors. Intracellular sphingosine 1-phosphate molecules are transported extracellularly and gain access to cognate receptors for autocrine and paracrine signaling and for signaling at distant sites reached through blood and lymphatic circulation systems. Intracellular pools of sphingosine 1-phosphate available for signaling are tightly regulated primarily by three enzymes: sphinosine kinase, S1P lyase and S1P phosphatase. Alterations in sphingosine 1-phosphate as well as the enzymes involved in its synthesis and catabolism have been observed in many types of malignancy. These enzymes are being evaluated for their role in mediating cancer formation and progression, as well as their potential to serve as targets of anti-cancer therapeutics. In this review, the impact of sphingosine 1-phosphate, its cognate receptors, and the enzymes of sphingosine 1-phosphate metabolism on cell survival, apoptosis, autophagy, cellular transformation, invasion, angiogenesis and hypoxia in relation to cancer biology and treatment are discussed.

Figure 1

S1P homeostasis is tightly regulated by the balance between its synthesis and degradation via three enzymes. (1) sphingosine kinase (Sphk), which generates S1P through phosphorylation of its precursor, (2) S1P phosphatases (SPP1 and SPP2), which reversibly convert S1P back to sphingosine, and (3) S1P lyase (SPL), which irreversibly degrades S1P to generate ethanolamine phosphate and hexadecenal, representing the last step in the sphingolipid degradation pathway.

Figure 2

A range of growth factors, hormones, angiogenic factor and other stimuli activate Sphk by phosphorylation, resulting in translocation of Sphk from cytosol to the plasma membrane. S1P is then generated and act intracellularly or exported out of the cells to engage with its receptors (S1P_1–5) to mediate mediates a diverse array of signaling pathways, impacting fundamental biological processes that are integral to cancer pathogenesis.