Export of sphingosine-1-phosphate and cancer progression

Abstract

Abbreviations: E2, estradiol; LEC, lymphatic endothelial cell; MRP, multidrug resistant protein; NF-B, nuclear factor-B; S1P, sphingosine-1-phosphate; SphK, sphingosine kinase; SPNS, spinster homolog; S1PR, sphingosine-1-phosphate receptor; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor .

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…Plasma membrane transporters of S1P have been identified and they include ABC transporter family members (ABCC1, ABCG2) (18) and the major facilitator superfamily member, Spinster 2 (Spns2) (19)(20)(21)(22). The "inside-out-signaling" process refers to the intracellular synthesis of S1P and transport out of the cell to activate S1PRs differentially expressed on mammalian cells activating autocrine and paracrine signaling (21). S1P levels are relatively high (1-2 M) in the blood and finely regulated.…”

Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts

“…While the role of ABC transporters in chemoresistance of cancers is widely recognized ( 1,8,15 ), the role of the enzymes that catalyze S1P formation and degradation in cancer growth and survival appears to be less clear. SphK1 is upregulated in many cancers, and cancer cells might have a "non-oncogene addiction" for this enzyme ( 16 ); however, new highly potent SphK1 and SphK1/2 inhibitors failed to inhibit cancer cell proliferation and growth of tumor xenografts in mice ( 17,18 ).…”

The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

“…"Inside-out" signaling refers to the process by which S1P produced inside cells is secreted by transporters and signals through its receptors (S1PRs) on the outside of cells. 5,7,25 Thus, S1P produced by SphK1-overexpressing cancer cells is a major source of S1P in the TME, which promotes cancer progression by "inside-out" signaling. S1P, produced by SphK2, and a portion produced by SphK1, acts intracellularly, although this is not thought to be associated with the TME directly.…”

“…5,7 For example, S1PR1 is important for B and T lymphocyte egression from secondary lymphatic organs such as lymph nodes. 5,16 In endothelial cells, S1PR1 and S1PR2 are essential in vascular development.…”

“…Cancer cells influence the surrounding microenvironment by releasing bioactive molecules, such as cytokines, chemokines, and lipid mediators. [6][7][8] Concurrently, non-cancer components in the TME, such as blood vessels, lymphatic vessels, and inflammatory cells, also provide bioactive molecules that influence cancer progression. These bioactive molecules secreted from both cancer and non-cancer cells in the TME have attracted attention as they are potential targets for molecular-targeted therapies or immunotherapies, such as anti-PD-1 therapy.…”