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Sphingosine‐1‐phosphate signaling in inflammation and cancer
Author(s) -
Spiegel Sarah
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.97.3
Subject(s) - s1pr1 , sphingosine kinase , sphingosine 1 phosphate receptor , sphingosine 1 phosphate , inflammation , sphingosine , sphingolipid , signal transduction , microbiology and biotechnology , kinase , receptor , fingolimod , sphingosine kinase 1 , biology , cancer research , immunology , biochemistry , multiple sclerosis , vascular endothelial growth factor a , vascular endothelial growth factor , vegf receptors
The sphingolipid metabolite sphingosine‐1‐phosphate (S1P) and the kinases that produce it have emerged as critical regulators of numerous fundamental biological processes important for inflammation and cancer. Activation of sphingosine kinases (SphKs) by a variety of agonists increases intracellular S1P. S1P can be secreted out of cells and bind to and signal through five specific G protein‐coupled receptors, designated S1PR1–5. It is now well established that this “inside‐out” signaling by S1P is important for many human diseases. The roles of the S1PRs in cell and organismal physiology will be discussed in detail and particularly their roles in chronic intestinal inflammation and colitis‐associated cancer (CAC). Focus will be on activation of SphK1 and how the SphK1‐S1P‐S1PR1 axis is at the nexus between NF‐κB and Stat3 and connects chronic inflammation and CAC. The development of inhibitors of SphK1 and small molecules that target specific subtypes of S1P receptors will also be discussed. The effectiveness of the pro‐drug FTY720 (known as Fingolimod or Gilenya), approved for the treatment of multiple sclerosis, has become the gold standard for S1P‐centric drugs, and will be used to illustrate the therapeutic value of modulating SphK1 and S1P receptor functions which holds great therapeutic promise. Supported by NIH grants R37GM043880, R01CA61774, and U19 AI077435.