Publication Date:
2011-10-07
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opitz, Christiane A -- Litzenburger, Ulrike M -- Sahm, Felix -- Ott, Martina -- Tritschler, Isabel -- Trump, Saskia -- Schumacher, Theresa -- Jestaedt, Leonie -- Schrenk, Dieter -- Weller, Michael -- Jugold, Manfred -- Guillemin, Gilles J -- Miller, Christine L -- Lutz, Christian -- Radlwimmer, Bernhard -- Lehmann, Irina -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21976023" target="_blank"〉PubMed〈/a〉
Keywords:
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/secretion
;
Ligands
;
Mice
;
Mice, Inbred C57BL
;
Mice, Nude
;
Neoplasm Transplantation
;
Paracrine Communication
;
Receptors, Aryl Hydrocarbon/immunology/*metabolism
;
Tryptophan/metabolism
;
Tryptophan Oxygenase/deficiency/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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