Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer

Cancer Cell. 2013 Jan 14;23(1):107-20. doi: 10.1016/j.ccr.2012.11.013. Epub 2012 Dec 27.

Abstract

Inflammatory bowel disease is an important risk factor for colorectal cancer. We show that sphingosine-1-phosphate (S1P) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of Sphk2. S1P 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 prodrug FTY720 decreased SphK1 and S1PR1 expression and eliminated the NF-κB/IL-6/STAT3 amplification cascade and development of CAC, even in Sphk2(-/-) mice, and may be useful in treating colon cancer in individuals with ulcerative colitis. Thus, the SphK1/S1P/S1PR1 axis is at the nexus between NF-κB and STAT3 and connects chronic inflammation and CAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology
  • Colitis / complications
  • Colitis / drug therapy
  • Colitis / genetics*
  • Colitis / pathology
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Fingolimod Hydrochloride
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / drug effects
  • Interleukin-6 / metabolism
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism
  • Lysophospholipids / physiology*
  • Mice
  • NF-kappa B / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Propylene Glycols / pharmacology
  • Propylene Glycols / therapeutic use
  • STAT3 Transcription Factor / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / genetics
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Sphingosine / physiology
  • Sphingosine / therapeutic use
  • Tumor Microenvironment / drug effects

Substances

  • Interleukin-6
  • Lysophospholipids
  • NF-kappa B
  • Propylene Glycols
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Fingolimod Hydrochloride
  • Sphingosine