Sphingosine-1-phosphate signaling and its role in disease

Abstract

The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) is now recognized as a critical regulator of many physiological and pathophysiological processes, including cancer, atherosclerosis, diabetes and osteoporosis. S1P is produced in cells by two sphingosine kinase isoenzymes, SphK1 and SphK2. Many cells secrete S1P, which can then act in an autocrine or paracrine manner. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. More recently, it was shown that S1P also has important intracellular targets involved in inflammation, cancer and Alzheimer's disease. This suggests that S1P actions are much more complex than previously thought, with important ramifications for development of therapeutics. This review highlights recent advances in our understanding of the mechanisms of action of S1P and its roles in disease.

Figure 1. Intracellular and extracellular actions of S1P

S1P produced intracellularly can inhibit functions of its pro-apoptotic precursor ceramide. Ceramide is implicated in growth arrest, apoptosis and autophagy (red quadrant). S1P also has intracellular targets (green quadrant) or can be exported out of cells to act in autocrine and/or paracrine manners through the S1P receptors (blue quadrant).

Figure 2. The pathobiology of S1P

S1P is implicated in numerous pathophysiological conditions and diseases that affect almost every organ in the human body. Because S1P is also linked to almost every type of cancer, only a few are shown.

Figure 3. Involvement of S1P in cancer

As described in the text, S1P regulates many processes in cancer cells and the tumor microenvironment that are important for malignant progression, including growth, survival and metastasis of the tumor, migration of stromal cells, and angiogenesis. S1P is also involved in recruitment of inflammatory cells and secretion of cytokines and chemokines that are important for inflammation and tumorigenesis.

Figure 4. Role of S1P and its receptors in atherogenesis

Binding of S1P to distinct S1P receptors regulates vascular tone and barrier function, monocyte attachment and migration, macrophage infiltration and retention, proliferation of smooth muscle cells, and activation of NF-κB leading to production of pro-inflammatory cytokines and adhesion molecules. S1PR1, red; S1PR2, green; S1PR3, blue.

Figure 5. Role of S1P in diabetes and obesity

Saturated fatty acid-induced insulin resistance is mediated by the proinflammatory receptor TLR4, which stimulates IKKβ and leads to NF-κB activation. This results in the upregulation of biosynthetic genes involved in de novo ceramide formation. Ceramide, in turn, inhibits Akt to induce apoptosis and suppress insulin function. Binding of adiponectin to its receptors enhances deacylation of ceramide to sphingosine, which can then be phosphorylated to form S1P. Inside-out signaling via S1PRs can activate AMPK, important for mitochondria biogenesis. S1P also stimulates Akt and prevents apoptosis.