Sphingosine-1-phosphate in chronic intestinal inflammation and cancer.

Abstract: Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes involved in inflammation and cancer. Here, we review the importance of S1P in colitis and colitis-associated cancer (CAC) and discuss our recent work demonstrating that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The effectiveness of the pro-drug FTY720 (known as fingolimod), 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. We will discuss our recent results showing that FTY720/fingolimod administration interferes with the SphK1/S1P/S1PR1 axis and suppresses the NF-κB/IL-6/Stat3 malicious amplification loop and CAC. These preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis. [Copyright &y& Elsevier]