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

Author

Listed:
  • Christiane A. Opitz

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ))

  • Ulrike M. Litzenburger

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ))

  • Felix Sahm

    (Institute of Pathology, University Hospital of Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ))

  • Martina Ott

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ))

  • Isabel Tritschler

    (University Hospital Zurich)

  • Saskia Trump

    (Helmholtz Center for Environmental Research)

  • Theresa Schumacher

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ))

  • Leonie Jestaedt

    (University Hospital of Heidelberg)

  • Dieter Schrenk

    (Food Chemistry and Toxicology, University of Kaiserslautern)

  • Michael Weller

    (University Hospital Zurich)

  • Manfred Jugold

    (Small Animal Imaging Center, German Cancer Research Center (DKFZ))

  • Gilles J. Guillemin

    (School of Medical Sciences, University of New South Wales)

  • Christine L. Miller

    (Johns Hopkins University)

  • Christian Lutz

    (Heidelberg Pharma AG)

  • Bernhard Radlwimmer

    (German Cancer Research Center (DKFZ))

  • Irina Lehmann

    (Helmholtz Center for Environmental Research)

  • Andreas von Deimling

    (Institute of Pathology, University Hospital of Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ))

  • Wolfgang Wick

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ))

  • Michael Platten

    (Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg
    Experimental Neuroimmunology Unit, German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • Christiane A. Opitz & Ulrike M. Litzenburger & Felix Sahm & Martina Ott & Isabel Tritschler & Saskia Trump & Theresa Schumacher & Leonie Jestaedt & Dieter Schrenk & Michael Weller & Manfred Jugold & G, 2011. "An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor," Nature, Nature, vol. 478(7368), pages 197-203, October.
    • Handle: RePEc:nat:nature:v:478:y:2011:i:7368:d:10.1038_nature10491
    DOI: 10.1038/nature10491
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    Cited by:

    1. Bo Wang & Jing Chen & Julia S. Caserto & Xi Wang & Minglin Ma, 2022. "An in situ hydrogel-mediated chemo-immunometabolic cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yun Seok Kim & Bongsub Ko & Da Jung Kim & Jihoon Tak & Chang Yeob Han & Joo-Youn Cho & Won Kim & Sang Geon Kim, 2022. "Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Niranjan Venkateswaran & Roy Garcia & M. Carmen Lafita-Navarro & Yi-Heng Hao & Lizbeth Perez-Castro & Pedro A. S. Nogueira & Ashley Solmonson & Ilgen Mender & Jessica A. Kilgore & Shun Fang & Isabella, 2024. "Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Donghong Zhang & Jinfeng Ning & Tharmarajan Ramprasath & Changjiang Yu & Xiaoxu Zheng & Ping Song & Zhonglin Xie & Ming-Hui Zou, 2022. "Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Pravin Kesarwani & Shiva Kant & Yi Zhao & Antony Prabhu & Katie L. Buelow & C. Ryan Miller & Prakash Chinnaiyan, 2023. "Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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