Dissecting the Role of the S1P/S1PR Axis in Health and Disease

Abstract

Sphingosine-1-phosphate (S1P) is a pleiotropic sphingophospholipid generated from the phosphorylation of sphingosine by sphingosine kinases (SPHKs). S1P has been experimentally demonstrated to modulate an array of cellular processes such as cell proliferation, cell survival, cell invasion, vascular maturation, and angiogenesis by binding with any of the five known G-protein-coupled sphingosine 1 phosphate receptors (S1P1-5) on the cell surface in an autocrine as well as a paracrine manner. Recent studies have shown that the S1P receptors (S1PRs) and SPHKs are the key targets for modulating the pathophysiological consequences of various debilitating diseases, such as cancer, sepsis, rheumatoid arthritis, ulcerative colitis, and other related illnesses. In this article, we recapitulate these novel discoveries relative to the S1P/S1PR axis, necessary for the proper maintenance of health, as well as the induction of tumorigenic, angiogenic, and inflammatory stimuli that are vital for the development of various diseases, and the novel therapeutic tools to modulate these responses in oral biology and medicine.

Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression

“…This may appear to contradict our earlier fi ndings; however, radiation pneumonitis and RIF are time-separate events with no active fi brogenesis going on at the pneumonitis stage of RILI. In fact, current fi ndings are well supported by the known profibrotic (36)(37)(38) and proliferative ( 40,42,43 ) role for the SphK1-S1P signaling axis, refl ecting the increased remodeling, the hallmark of fi brogenesis, in RIF lungs.…”

Sphingosine Kinase 1 Regulates Tumor Necrosis Factor-mediated RANTES Induction through p38 Mitogen-activated Protein Kinase but Independently of Nuclear Factor κB Activation

“…The generation of S1P by SK1 can exert its signaling effects through two routes. In the first, S1P is exported to the outer leaflet via transporter proteins (8,9), where it can act on any of five identified G-protein-coupled receptors (S1P receptors 1-5) (10). Alternatively, S1P is also thought to function as an intracellular signaling molecule acting directly on intracellular targets.…”

Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma

“…Among these, S1P 1 and S1P 2 are widely expressed in most tissues; S1P 3 is highly expressed in the heart, lung, spleen, kidney, intestine, and diaphragm; S1P 4 is specifically expressed in lymphoid tissues and is highly expressed in blood cells, whereas S1P 5 is restricted to the brain and skin and is highly expressed in natural killer cells (Aarthi et al, 2011). Existing studies have shown that the S1P/sphingosine-1-phosphate receptor (S1PR) axis plays critical roles in a wide variety of physiologic and pathophysiological processes, including cancer.…”