• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • A rate limiting step in


    A rate-limiting step in the generation of kynurenine and xanthurenic d-biotin is the oxidation of N-formyl-kynurenine to l-kynurenine via indolamine 2,3-dioxygenase (IDO) or tryptophan dioxygenase (TDO). IDO and/or TDO knockdown decreases and ectopic over-expression increases production of endogenous AHR ligands and AHR activity in tumor lines [35,42,50], suggesting that these enzymes are rate-limiting in the control of AHR activity. Notably, IDO is regulated by the AHR in dendritic cells [53–55]. Similarly, baseline IDO and TDO levels are maintained, at least in part, in breast cancer cells by constitutively active AHR, i.e., AHR driven by endogenous tryptophan-derived ligands [35]. Therefore, constitutive AHR activity in cancers may be mediated by an amplification loop in which the IDO/TDO-dependent AHR ligands in the kynurenine pathway drive AHR activity, which in turn induces IDO and/or TDO yielding the generation of more endogenous AHR agonist(s) (Figure 2). Although not yet directly shown, this model suggests the possibility that non-genotoxic environmental AHR ligands, such as TCDD, may initiate and/or exacerbate a self-sustaining AHR signaling loop. The aforementioned loop may be further amplified by the production of AHR ligands through the kynurenine pathway in the non-malignant cells of the tumor microenvironment. For example, cancer stroma [35,51,56–58], infiltrating dendritic cells, and regulatory T cells (Tregs) express TDO and/or IDO and produce AHR ligands [59,60]. Consequently, malignant cells may be bathed in a microenvironment saturated with tryptophan-derived metabolites, several of which (kynurenine, kynurenic acid, xanthurenic acid, cinnabarinic acid) [61]) are AHR ligands. Of note, IDO- and TDO- are being targeted for cancer therapy because of their role in immunosuppression. The contribution of the AHR→IDO/TDO→AHR ligand pathway in suppressing tumor immunity is discussed in section 4 below.
    The AHR as a potential immune checkpoint inhibitor
    Consequences of constitutive AHR activity
    Still to be resolved: Should the AHR be targeted with exogenous agonists or antagonists in the cancer setting? Studies described above provide strong evidence that constitutively active AHR promotes tumor formation and the induction of an aggressive phenotype. That said, very little that we learn about AHR signaling appears simple and clear cut. Thus, some studies suggest that the AHR may function in the opposite manner, as a tumor suppressor. For example, mice lacking the AHR are more likely to develop liver tumors after exposure to diethylnitrosamine (a hepatic carcinogen) than wild type mice [95]. Prostate cancer-prone TRAMP (transgenic adenocarcinoma of the mouse prostate) mice experience an increase in severity and frequency of prostate cancers if the AHR is knocked out [96]. Conversely, treatment of TRAMP mice with the AHR ligand 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF) reduces the frequency of prostate metastases [46]. AHR may also play a protective role in colitis-associated colorectal tumorigenesis [97,98] and in melanoma [99,100]. Finally, AHR activation with some exogenous ligands may reduce breast cancer growth and/or metastasis [101–103]. These results, and those showing repression of tumor formation or progression by the AHR, demonstrate the complexity of AHR-mediated pathways and what may be exogenous and endogenous ligand-, cell- and tumor-type-specific differences in AHR signaling. The challenge for the future will be in defining how different AHR ligands can elicit different genomic and functional outcomes and in deciphering how tissue-specific transcriptional regulators can modify AHR signaling to result in a myriad of complex and sometimes contradictory outcomes.
    Acknowledgements This work was supported by the National Institute of Environmental Health SciencesP42ES007381 and grants from the Art BeCAUSE Breast Cancer Foundation and the Avon Foundation for Women (Avon Breast Cancer Crusade award no. 02-2015-028).