title: IDO1 metabolites activate β-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice.
abstract: OBJECTIVE
  Indoleamine 2,3 dioxygenase-1 (IDO1) catabolizes tryptophan along the kynurenine pathway. Although IDO1 is expressed in inflamed and neoplastic epithelial cells of the colon, its role in colon tumorigenesis is not well understood. We used genetic and pharmacologic approaches to manipulate IDO1 activity in mice with colitis-associated cancer and human colon cancer cell lines.
  
  
  METHODS
  C57Bl6 wild-type (control), IDO1-/-, Rag1-/-, and Rag1/IDO1 double-knockout mice were exposed to azoxymethane and dextran sodium sulfate to induce colitis and tumorigenesis. Colitis severity was assessed by measurements of disease activity, cytokine levels, and histologic analysis. In vitro experiments were conducted using HCT 116 and HT-29 human colon cancer cells. 1-methyl tryptophan and small interfering RNA were used to inhibit IDO1. Kynurenine pathway metabolites were used to simulate IDO1 activity.
  
  
  RESULTS
  C57Bl6 mice given pharmacologic inhibitors of IDO1 and IDO1-/- mice had lower tumor burdens and reduced proliferation in the neoplastic epithelium after administration of dextran sodium sulfate and azoxymethane than control mice. These reductions also were observed in Rag1/IDO1 double-knockout mice compared with Rag1-/- mice (which lack mature adaptive immunity). In human colon cancer cells, blockade of IDO1 activity reduced nuclear and activated β-catenin, transcription of its target genes (cyclin D1 and Axin2), and, ultimately, proliferation. Exogenous administration of IDO1 pathway metabolites kynurenine and quinolinic acid led to activation of β-catenin and proliferation of human colon cancer cells, and increased tumor growth in mice.
  
  
  CONCLUSIONS
  IDO1, which catabolizes tryptophan, promotes colitis-associated tumorigenesis in mice, independent of its ability to limit T-cell-mediated immune surveillance. The epithelial cell-autonomous survival advantage provided by IDO1 to colon epithelial cells indicate its potential as a therapeutic target.
authors.affiliation: Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Ameet I
authors.initials: AI
authors.lastname: Thaker
authors.forename: M Suprada
authors.initials: MS
authors.lastname: Rao
authors.forename: Kumar S
authors.initials: KS
authors.lastname: Bishnupuri
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kerr
authors.forename: Lynne
authors.initials: L
authors.lastname: Foster
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Marinshaw
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Newberry
authors.forename: William F
authors.initials: WF
authors.lastname: Stenson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Ciorba
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000378:metabolism / Q000503:physiopathology*; D003093:Colitis, Ulcerative; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000209:etiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D045325:HCT116 Cells; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000503:physiopathology*; D007737:Kynurenine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017378:Quinolinic Acid / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000187:drug effects* / Q000502:physiology
chemical_list: D002273:Carcinogens; D018398:Homeodomain Proteins; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051176:beta Catenin; C064658:RAG-1 protein; D007737:Kynurenine; D017378:Quinolinic Acid; D001397:Azoxymethane
keywords: 1-mT; 1-methyl tryptophan; AOM; APC; CAC; CRC; DSS; DbKO; GCN; IBD; IDO; IFN; Metabolism; Mouse Model; Ulcerative Colitis; antigen-presenting cell; azoxymethane; colitis-associated cancer; colorectal cancer; dextran sodium sulfate; double gene knockout mouse for indoleamine 2,3 dioxygenase 1 and Rag 1; general control nonrepressed; indoleamine 2,3 dioxygenase; inflammatory bowel disease; interferon