An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor
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DOI：
10.1038/nature10491
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发表时间：
2011-10-13
期刊：
影响因子：
64.8
通讯作者：
Platten, Michael
中科院分区：
文献类型：
--
作者：
Opitz, Christiane A.;Litzenburger, Ulrike M.;Platten, Michael
芳烃受体（AHR）被环境异生有毒化学物质例如2，3，7，8-四氯二苯并-p-二恶英（二恶英）激活，已经涉及多种细胞过程，例如胚胎发生、转化、肿瘤发生和炎症。但是，在生理条件下，在没有环境有毒化学物质的情况下激活AHR的内源性配体的身份仍然是未知的。在这里，我们确定色氨酸（Trp）分解代谢产物犬尿氨酸（Kyn）作为人类AHR的内源性配体，其由人类肿瘤细胞通过色氨酸-2，3-双加氧酶（TDO）组成性产生，TDO是一种肝脏和神经元来源的Trp降解酶，尚未参与癌症生物学。TDO衍生的Kyn抑制抗肿瘤免疫应答，并以自分泌/旁分泌方式通过AHR促进肿瘤细胞存活和运动。TDO-AHR通路在人脑肿瘤中是活跃的，并且与恶性进展和较差的存活率相关。由于Kyn是在局部微环境的癌症进展和炎症过程中产生的，其量足以激活人类AHR，因此这些结果为之前未识别的AHR病理生理功能提供了证据，对癌症和免疫生物学具有深远的影响。
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.