(original) (raw)

TY - JOUR AU - Opitz, Christiane A. AU - Litzenburger, Ulrike M. AU - Sahm, Felix AU - Ott, Martina AU - Tritschler, Isabel AU - Trump, Saskia AU - Schumacher, Theresa AU - Jestaedt, Leonie AU - Schrenk, Dieter AU - Weller, Michael AU - Jugold, Manfred AU - Guillemin, Gilles J. AU - Miller, Christine L. AU - Lutz, Christian AU - Radlwimmer, Bernhard AU - Lehmann, Irina AU - von Deimling, Andreas AU - Wick, Wolfgang AU - Platten, Michael PY - 2011 DA - 2011/10/01 TI - An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor JO - Nature SP - 197 EP - 203 VL - 478 IS - 7368 AB - 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. SN - 1476-4687 UR - https://doi.org/10.1038/nature10491 DO - 10.1038/nature10491 ID - Opitz2011 ER -