Roles of sphingosine 1-phosphate on tumorigenesis

Figure 1 Sphingolipid structure and metabolism. All sphingolipids contain a long chain base. Sphingomyelin (SM) is metabolized to ceramide by sphingomyelinase. Ceramide is further metabolized to sphingosine and sphingosine 1-phosphate (S1P) by ceramidase and sphingosine kinases (SphKs), respectively. Subsequently, S1P is irreversibly degraded to hexadecenal and ethanolamine phosphate by S1P ligase (SPL). S1P can be recycled to sphingosine and then ceramide by S1P phosphatase (S1PP) and ceramide synthase, respectively.

Figure 2 Ceramide-sphingosine-sphingosine 1-phosphate rheostat model. Ceramide, sphingosine, and sphingosine 1-phosphate (S1P) with opposing functions are interconvertible within cells. The balance between ceramide/sphingosine and S1P forms a sphingolipid rheostat model, that is primed for cell death when the balance shifts towards ceramide or sphingosine, or to cell survival or proliferation when S1P levels are increased. This rheostat model also regulates autophagic cell death or survival through targeting to Beclin 1 which interacts with Bcl-2 protein.

Figure 3 Sphingosine 1-phosphate receptor subtype-specific signaling. Sphingosine 1-phosphate (S1P)₁, S1P₂, S1P₃, and S1P₅ activate partially overlapping downstream signaling via coupling different G proteins and then regulate several biological functions, such as cell proliferation, migration, angiogenesis, and autophagy. Through coupling to G_i protein, S1P₁ activates extracellular signal-regulated kinase (ERK)1/2, Rac, and phosphoinositide 3-kinase (PI3K) signaling to regulate cell proliferation, migration, and angiogenesis, respectively. S1P₂ mediates inhibition of cell migration via G_12/13-Rho signaling, whereas S1P₃ enhances cell migration and angiogenesis through G_i-Rac and G_q-phospholipase C (PLC) signaling, respectively. Our unpublished results have revealed that G_i coupled-S1P₅ induces autophagy which is mediated through PI3K and PLC signaling.