An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.

Abstract

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

• Authors: Christiane A Opitz, Ulrike M Litzenburger, Felix Sahm, Martina Ott, Isabel Tritschler, Saskia Trump, Theresa Schumacher, Leonie Jestaedt, Dieter Schrenk, Michael Weller, Manfred Jugold, Gilles J Guillemin, Christine L Miller, Christian Lutz, Bernhard Radlwimmer, Irina Lehmann, Andreas von Deimling, Wolfgang Wick, Michael Platten
• Journal: Nature (Nature) Vol. 478 Issue 7368 Pg. 197-203 (Oct 05 2011) ISSN: 1476-4687 [Electronic] England
• PMID: 21976023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Receptors, Aryl Hydrocarbon
• Kynurenine
• Tryptophan
• Tryptophan Oxygenase

Topics

• Animals
• Autocrine Communication
• Brain Neoplasms (genetics, immunology, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Glioma (genetics, immunology, metabolism, pathology)
• Humans
• Kynurenine (immunology, metabolism, pharmacology)
• Ligands
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasm Transplantation
• Paracrine Communication
• Receptors, Aryl Hydrocarbon (immunology, metabolism)
• Tryptophan (metabolism)
• Tryptophan Oxygenase (deficiency, genetics, metabolism)