The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value

Román, Ángel; Carvajal-González, José María; Merino, Jaime M.; Mulero‐Navarro, Sonia; Fernández-Salguero, Pedro M.

doi:10.1016/j.pharmthera.2017.12.003

Cited by 75 publications

(61 citation statements)

References 200 publications

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“…However additional AhR functionality has been revealed in the suppression of the adaptive immune response by numerous environmental contaminants; the correct functioning of the female reproductive system at all stages from fetal development through to adulthood, homeostasis of the hepatic, vascular, and cardiovascular symptoms; and as a modulator of antiviral immunity . Recent studies have also elucidated the cellular roles of the AhR in functional interactions with various signaling pathways (including the ER) and its physiological role in the regulation of many cellular processes including cell proliferation, the cell cycle, pluripotency, and stemness …”

Section: Functionmentioning

confidence: 99%

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

Baker

Sakoff

McCluskey

2019

Medicinal Research Reviews

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Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triplenegative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic-to-nuclear pathway of the AhR for the possible future treatment of breast cancer. K E Y W O R D S aryl hydrocarbon receptor, breast cancer, cancer drugs Abbreviations: 3MC, 3-methylcholanthrene; AF, aminoflavone; AF-1, activation function domain 1; AF-2, activation function domain 2; AhR, aryl hydrocarbon receptor; AhRR, aryl hydrocarbon receptor repressor; AIP, aryl hydrocarbon receptor-interacting protein; ANI-7, (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile; ARNT, aryl hydrocarbon receptor nuclear translocator; BaP, benzo[a]pyrene; BE, botanical estrogen; bHLH, basic helixloop-helix; βNF, β-naphthoflavone; BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; DNF, dinaphtho[1,2-b;1′2'-d] furan; ER, estrogen receptor; FDA, US Food and Drug Administration; FICZ, 6-formylindolo[3,2-b]carbazole; HAHs, halogenated aromatic hydrocarbons; HER-2, human epidermal growth factor receptor 2; HR, hormone receptor; Hsp90, heat shock protein 90; ITE, 2-(1′H-indole-3′-carbonyl)-thiazole-4carboxylic acid ester; LBD, ligand-binding domain; NLS, nuclear localization sequences; NSAID, nonsteroidal anti-inflammatory drug; p23, prostaglandin E synthase 3; PAHs, polycyclic aromatic hydrocarbons; PAS, period-aryl hydrocarbon receptor nuclear translocator-single minded; PAS-A, period-aryl hydrocarbon receptor nuclear translocator-single minded domain A; PAS-B, period-aryl hydrocarbon receptor nuclear translocator-single minded domain B; PCB, 3,3′,4,4′,5-pentachlorobiphenyl; PPI, proton pump inhibitor; PR, progesterone receptor; PR-A, progesterone receptor form A; PR-B, progesterone receptor form B; PR-C, progesterone receptor form C; ROS, reductive oxidative species; SERMs, selective estrogen receptor modulators; SULT1A1, sulfotransferase 1A1; TAD, transactivation domain; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, 2,3,7,8-tetrachlorodibenzofuran; TNBC, triplenegative breast cancer; Tregs, regulatory T cells; XAP-2, hepatitis B virus X-associated protein 2; XRE, xenobiotic response element. | BREAST CANCER BACKGROUNDBreast cancer is the most common cancer in women. Of...

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Section: Functionmentioning

confidence: 99%

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

Baker

Sakoff

McCluskey

2019

Medicinal Research Reviews

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“…The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and a structurally diverse range of chemicals [1,2]. In normal physiology, the AhR appears to be important in development; it plays a key regulatory role in immune responses and disease [1,[3][4][5][6]. Numerous endogenous ligands of the AhR have been proposed, and while none have been established with certainty, tryptophan and indole metabolites are likely candidates [1,2,7,8].…”

Section: Introductionmentioning

confidence: 99%

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Soshilov

Motta

Bonati

et al. 2020

IJMS

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of an AhR lacking the entire PASB structurally diverse chemicals, including halogenated aromatic hydrocarbons. Ligand-dependent transformation of the AhR into its DNA binding form involves a ligand-dependent conformational change, heat shock protein 90 (hsp90), dissociation from the AhR complex and AhR dimerization with the AhR nuclear translocator (ARNT) protein. The mechanism of AhR transformation was examined using mutational approaches and stabilization of the AhR:hsp90 complex with sodium molybdate. Insertion of a single mutation (F281A) in the hsp90-binding region of the AhR resulted in its constitutive (ligand-independent) transformation/DNA binding in vitro. Mutations of AhR residues within the Arg-Cys-rich region (R212A, R217A, R219A) and Asp371 (D371A) impaired AhR transformation without a significant effect on ligand binding. Stabilization of AhR:hsp90 binding with sodium molybdate decreased transformation/DNA binding of the wild type AhR but had no effect on constitutively active AhR mutants. Interestingly, transformation of the AhR in the presence of molybdate allowed detection of an intermediate transformation ternary complex containing hsp90, AhR, and ARNT. These results are consistent with a stepwise transformation mechanism in which binding of ARNT to the liganded AhR:hsp90 complex results in a progressive displacement of hsp90 and conversion of the AhR into its high affinity DNA binding form. The available molecular insights into the signaling mechanism of other Per-ARNT-Sim (PAS) domains and structural information on hsp90 association with other client proteins are consistent with the proposed transformation mechanism of the AhR.

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“…In the canonical AhR signaling pathway, cytosolic AhR translocates into the nucleus upon binding of the ligand, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT; NCBI gene ID: 25242), Then, the protein dimer binds directly or indirectly with DNA consensus sequence elements (termed AhR-, dioxin-, or xenobiotic-response elements: AhRE, DRE, or XRE), containing the core sequence 5'-GCGTG-3', located in the 5'-regulatory region of dioxin-response genes, including cytochrome P4501A1 (CYP1A1), CYP1B1, the aryl hydrocarbon receptor repressor (AHRR; NCBI gene ID: 498999), indoleamine 2,3-dioxygenase 1 (Ido1; NCBI gene ID: 66029), and nuclear factors, erythoid 2-like 2 (Nfe2l2; NCBI gene ID: 83619), in an asymmetric manner [18][19][20][21][22][23]. The activation of the AhR signal pathway by the cellular responses against environmental toxins and carcinogens elicits hepatotoxicity and tumor propagation in liver [24][25][26]. In particular, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to be effectively promote liver tumor by binding with AhR [26,27].…”

Section: Introductionmentioning

confidence: 99%

Prediction Model of Aryl Hydrocarbon Receptor Activation by a Novel QSAR Approach, DeepSnap–Deep Learning

et al. 2020

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that senses environmental exogenous and endogenous ligands or xenobiotic chemicals. In particular, exposure of the liver to environmental metabolism-disrupting chemicals contributes to the development and propagation of steatosis and hepatotoxicity. However, the mechanisms for AhR-induced hepatotoxicity and tumor propagation in the liver remain to be revealed, due to the wide variety of AhR ligands. Recently, quantitative structure–activity relationship (QSAR) analysis using deep neural network (DNN) has shown superior performance for the prediction of chemical compounds. Therefore, this study proposes a novel QSAR analysis using deep learning (DL), called the DeepSnap–DL method, to construct prediction models of chemical activation of AhR. Compared with conventional machine learning (ML) techniques, such as the random forest, XGBoost, LightGBM, and CatBoost, the proposed method achieves high-performance prediction of AhR activation. Thus, the DeepSnap–DL method may be considered a useful tool for achieving high-throughput in silico evaluation of AhR-induced hepatotoxicity.

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The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value

Cited by 75 publications

References 200 publications

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form

Prediction Model of Aryl Hydrocarbon Receptor Activation by a Novel QSAR Approach, DeepSnap–Deep Learning

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