IDO1 metabolites activate β-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice

Gastroenterology. 2013 Aug;145(2):416-25.e1-4. doi: 10.1053/j.gastro.2013.05.002. Epub 2013 May 10.

Abstract

Background & aims: 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.

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.

Publication types

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

MeSH terms

  • Animals
  • Azoxymethane
  • Carcinogens
  • Cell Proliferation / drug effects
  • Colitis / metabolism
  • Colitis / physiopathology*
  • Colitis, Ulcerative
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / etiology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology*
  • HCT116 Cells
  • HT29 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / physiology*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / physiopathology*
  • Kynurenine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Quinolinic Acid / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • beta Catenin / drug effects*
  • beta Catenin / physiology

Substances

  • Carcinogens
  • Homeodomain Proteins
  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • beta Catenin
  • indoleamine 2,3-dioxygenase 1, human
  • RAG-1 protein
  • Kynurenine
  • Quinolinic Acid
  • Azoxymethane