title: Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liang
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Kuzhuvelil B
authors.initials: KB
authors.lastname: Harikumar
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Yamada
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Huang
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Allegood
authors.forename: Megan M
authors.initials: MM
authors.lastname: Price
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kordula
authors.forename: Sheldon
authors.initials: S
authors.lastname: Milstien
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D003092:Colitis / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000068876:Fingolimod Hydrochloride; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D015850:Interleukin-6; D008246:Lysophospholipids; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D050796:STAT3 Transcription Factor; D013110:Sphingosine; D000099157:Sphingosine Kinase; C494087:Stat3 protein, mouse; C060506:sphingosine 1-phosphate