Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of cancer progression. Although some important roles of intracellular S1P have recently been uncovered, the majority of its biological effects are known to be mediated via activation of five specific G protein-coupled receptors [S1P receptor (S1PR)1-S1PR5] located on the cell surface. Secretion of S1P produced inside cells by sphingosine kinases can then signal through these receptors in autocrine, paracrine, and/or endocrine manners, coined "inside-out" signaling of S1P. Numerous studies suggest that secreted S1P plays important roles in cancer progression; thus, understanding the mechanism by which S1P is exported out of cells, particularly cancer cells, is both interesting and important. Here we will review the current understanding of the transport of S1P out of cancer cells and its potential roles in the tumor microenvironment.
Highlights
Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of cancer progression
We have recently extended these observations and shown that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-kB-regulated cytokine IL-6, persistent activation of the transcription factor STAT3, and consequent upregulation of the S1P receptor (S1PR), S1PR1
Major progress has been made in our current understanding of the mechanisms by which S1P regulates cell growth and survival, migration, and angiogenesis by inside-out signaling through S1PRs in autocrine, paracrine, and/or endocrine manners
Summary
Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of cancer progression. An excellent example is the contributions of blood endothelial cells in tumor-induced angiogenesis in cancer progression [2]. SphK1 is a critical regulator of the S1P rheostat and produces S1P that functions in inside-out signaling by activation of the S1P receptors (S1PRs).
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