Roles of sphingosine 1-phosphate on tumorigenesis

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with a variety of biological activities. It is generated from the conversion of ceramide to sphingosine by ceramidase and the subsequent conversion of sphingosine to S1P, which is catalyzed by sphingosine kinases. Through increasing its intracellular levels by sphingolipid metabolism and binding to its cell surface receptors, S1P regulates several physiological and pathological processes, including cell proliferation, migration, angiogenesis and autophagy. These processes are responsible for tumor growth, metastasis and invasion and promote tumor survival. Since ceramide and S1P have distinct functions in regulating in cell fate decision, the balance between the ceramide/sphingosine/S1P rheostat becomes a potent therapeutic target for cancer cells. Herein, we summarize our current understanding of S1P signaling on tumorigenesis and its potential as a target for cancer therapy.

Potential signaling pathway involved in sphingosine-1-phosphate-induced epithelial-mesenchymal transition in cancer

“…S1P is a ligand for the S1P-specific G-protein coupled receptors, termed S1P [1][2][3][4][5] . The effects of S1P on cell invasion, motility and migration are mediated via receptor-dependent pathways (12,(39)(40)(41). In general, S1P 1 is exclusively coupled with G i protein to activate cell migration through extracellular signal-regulated kinase, PI3K, Akt, phospholipase C and Rac signaling (42)(43)(44).…”

“…In general, S1P 1 is exclusively coupled with G i protein to activate cell migration through extracellular signal-regulated kinase, PI3K, Akt, phospholipase C and Rac signaling (42)(43)(44). The S1P 2 and S1P 3 receptors could couple with the G i , G q and G 12/13 proteins to inhibit cell migration via ρ signaling (41,45). S1P modulates the levels of MMPs, such as MMP-2 and MMP-9, regulating cell invasion (46)(47)(48).…”

Involvement of Sphingosine Kinases/Sphingosine-1-Phosphate (S1P)/S1P Receptors in Breast Cancer Subtypes

“…Ceramide can be hydrolyzed by actions of many ceramidases into sphingosine, which in turn is phosphorylated by SphK to form S1P. S1P can either act via S1PRs at membrane surface to regulate downstream signaling or be degraded irreversibly in the endoplasmic reticulum by S1P lyase [11,30,31]. Ceramide, sphingosine and S1P are readily inter-convertible and the balance between these sphingolipids is tightly regulated by SphKs, S1P phosphatase and type 2 phosphatidate phosphohydrolase.…”

“…SphK1 has been shown to be overexpressed in many human tumors, including breast cancer, where it contributes to malignant progression [6,32,33]. SphK1 is predominantly located in the cytosol and can be stimulated by various growth factors and cytokines [7,31,34]. When SphK1 is activated through phosphorylation at residue Ser225 by ERK, it is translocated to the plasma membrane where it preferentially acts on its substrate, sphingosine [7,31].…”

“…SphK1 is predominantly located in the cytosol and can be stimulated by various growth factors and cytokines [7,31,34]. When SphK1 is activated through phosphorylation at residue Ser225 by ERK, it is translocated to the plasma membrane where it preferentially acts on its substrate, sphingosine [7,31]. S1P generated by this process at the inner leaflet can function intracellularly as a second messenger or it can be exported out of the cell through ABCC1 transporter and then bind to S1PRs with high affinity in an autocrine and/or paracrine manner to promote proliferation, migration and angiogenesis [7,10,11,35,36].…”