Role of the aryl hydrocarbon receptor in carcinogenesis and potential as a drug target
TL;DR: It is shown that selective AHR modulators that exhibit agonist or antagonist activities represent an important new class of anticancer agents that can be directed against multiple tumors.
About: This article is published in Toxicological Sciences.The article was published on 2013-09-01 and is currently open access. It has received 235 citations till now. The article focuses on the topics: Aryl hydrocarbon receptor & Cellular homeostasis.
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01 Jan 1996
TL;DR: The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin this paper.
Abstract: The Ah receptor (AHR) is a ligand-activated transcription factor that mediates a pleiotropic response to environmental contaminants such as benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. In an effort to gain in- sight into the physiological role of the AHR and to develop models useful in risk assessment, gene targeting was used to inactivate the murine Ahr gene by homologous recombination. Ahr 2/2 mice are viable and fertile but show a spectrum of hepatic defects that indicate a role for the AHR in normal liver growth and development. The Ahr 2/2 phenotype is most severe between 0-3 weeks of age and involves slowed early growth and hepatic defects, including reduced liver weight, transient microvesicular fatty metamorphosis, prolonged extramedul- lary hematopoiesis, and portal hypercellularity with thicken- ing and fibrosis.
800 citations
TL;DR: Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus, which suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression.
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as ‘dioxin’. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours.
629 citations
TL;DR: The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligand-mediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract.
395 citations
Cites background from "Role of the aryl hydrocarbon recept..."
...The involvement of AHR in inflammatory signaling and cell cycle progression suggests it may play a role in various stages of tumorigenesis (Gasiewicz et al., 2008; Safe et al., 2013; Murray et al., 2014)....
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...progression suggests it may play a role in various stages of tumorigenesis (Gasiewicz et al., 2008; Safe et al., 2013; Murray et al., 2014)....
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TL;DR: The role of AhR for immune cells of the barrier organs: skin, gut, and lung is discussed and the current two prevailing views—namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for Ahr as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands are discussed.
Abstract: The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim-basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views-namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance.
366 citations
Cites background from "Role of the aryl hydrocarbon recept..."
...(Safe et al., 2013)....
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...VI. Therapeutic Potential of Aryl Hydrocarbon Receptor Ligands The therapeutic potential of the AhR has been recognized early, especially in the context of cancer (Safe et al., 1999, 2013)....
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...Thus, selective aryl hydrocarbon receptor modulators (SAhRMs) have been developed with a view to clinical applications (Safe et al., 2013)....
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TL;DR: It is suggested that polar PAHs could have serious toxicological effects on human health and should be considered during risk assessment of PAH-contaminated sites and critical knowledge gaps and future research requirements are discussed.
208 citations
References
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TL;DR: The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data and provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-power gene expression and genomic hybridization experiments.
Abstract: The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expression databases that benefit from coherent data sets, and which are constructed to facilitate a particular analytic method, but rather complement these by acting as a tertiary, central data distribution hub. The three central data entities of GEO are platforms, samples and series, and were designed with gene expression and genomic hybridization experiments in mind. A platform is, essentially, a list of probes that define what set of molecules may be detected. A sample describes the set of molecules that are being probed and references a single platform used to generate its molecular abundance data. A series organizes samples into the meaningful data sets which make up an experiment. The GEO repository is publicly accessible through the World Wide Web at http://www.ncbi.nlm.nih.gov/geo.
10,968 citations
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Abstract: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
6,417 citations
"Role of the aryl hydrocarbon recept..." refers background in this paper
...Downloaded from https://academic.oup.com/toxsci/article-abstract/135/1/1/1659415/Role-of-the-Aryl-Hydrocarbon-Receptor-in by guest on 16 September 2017 growth of melanoma cancer cells overexpressing NRAS (Barretina et al., 2012), decreased urothelial cancer T24 cell invasion and MMP-9 expression (Portal-Nunez et al., 2012), decreased expression of fibroblast growth factor-9 and osteopontin in lung cancer cells (Chuang et al., 2012; Wang et al., 2009), decreased C4-2 (androgen independent) prostate cancer cell growth (Tran et al., 2013), decreased DAOY medulloblastoma cell growth, and induced G 0 /G 1 arrest (p27 is also induced) (Dever and Opanashuk, 2012)....
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...…by guest on 16 September 2017 growth of melanoma cancer cells overexpressing NRAS (Barretina et al., 2012), decreased urothelial cancer T24 cell invasion and MMP-9 expression (Portal-Nunez et al., 2012), decreased expression of…...
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TL;DR: The toxicity of halogenated aromatic hydrocarbons appears to be due to the sustained expression of a normal cellular regulatory system, of which the author was previously unaware.
Abstract: In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.
2,536 citations
"Role of the aryl hydrocarbon recept..." refers background in this paper
...…is required for inducing the prototypical toxic effects of TCDD and structurally related HAs, even though the molecular mechanisms and genes associated with toxicities such as chloracne, wasting syndrome, tumor promotion, and others are not well defined (Poland and Knutson, 1982; Whitlock, 1999)....
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...…role for the receptor in mediating the toxicities of HAs and polynuclear aromatic hydrocarbons (PAHs), and thus, the AHR became inextricably linked to two of the most prominent classes of environmental toxicants (Goldstein et al., 1989; Nebert et al., 1975; Poland and Knutson, 1982; Safe, 1986)....
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TL;DR: The identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of Treg and TH17 cell differentiation in mice is reported, constituting a unique target for therapeutic immunomodulation.
Abstract: Regulatory T cells (Treg) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of Treg cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (TH17). Although Treg cell dysfunction and/or TH17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of Treg and TH17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional Treg cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with Treg cell development, boosted TH17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both Treg and TH17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation. The aryl hydrocarbon receptor (AHR) is a transcription factor best known for mediating the toxicity of aromatic hydrocarbons such as dioxin: its activation leads to the production of detoxification enzymes. AHR has been intensely studied in relation to toxicology and cancer research, but no mechanistic connection to the immune system was known. Now two groups report a role for AHR in maintaining the balance between two T-lymphocyte populations — the Treg and TH17 cells — that are part of the immune regulation system dealing with tolerance of self-antigens and pathogen clearance. Both groups also show that AHR affects the severity of experimental autoimmune encephalitis, a mouse model of multiple sclerosis. This work raises the possibility that stimulation of AHR by environmental factors could be involved in the development of autoimmune disease, and point to AHR as a possible drug target for immunomodulation. The aryl hydrocarbon receptor (AHR) is the cellular receptor for a number of environment contaminants. It is shown here to induce regulatory T cells when bound to the ligand TCCD and promote TH17 differentiation when bound to FICZ.
1,572 citations
TL;DR: It is shown that in the CD4+ T-cell lineage of mice AHR expression is restricted to the TH17 cell subset and its ligation results in the production of the TH16 cytokine interleukin (IL)-22, and AHR ligands may represent co-factors in the development of autoimmune diseases.
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor best known for mediating the toxicity of dioxin. Environmental factors are believed to contribute to the increased prevalence of autoimmune diseases, many of which are due to the activity of T(H)17 T cells, a new helper T-cell subset characterized by the production of the cytokine IL-17. Here we show that in the CD4+ T-cell lineage of mice AHR expression is restricted to the T(H)17 cell subset and its ligation results in the production of the T(H)17 cytokine interleukin (IL)-22. AHR is also expressed in human T(H)17 cells. Activation of AHR by a high-affinity ligand during T(H)17 cell development markedly increases the proportion of T(H)17 T cells and their production of cytokines. CD4+ T cells from AHR-deficient mice can develop T(H)17 cell responses, but when confronted with AHR ligand fail to produce IL-22 and do not show enhanced T(H)17 cell development. AHR activation during induction of experimental autoimmune encephalomyelitis causes accelerated onset and increased pathology in wild-type mice, but not AHR-deficient mice. AHR ligands may therefore represent co-factors in the development of autoimmune diseases.
1,541 citations
"Role of the aryl hydrocarbon recept..." refers background in this paper
...b]carbazole (FICZ) increased, the severity of EAE in mice (Veldhoen et al., 2008)....
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