Emerging evidence suggests that ahr is a key sensor allowing immune cells to adapt to. It was originally thought to function primarily as a sensor of xenobiotic chemicals and also as the regulator of enzymes such as cytochrome p450s that metabolize these chemicals. Selective ah receptor ligands mediate enhanced srebp1. The aryl hydrocarbon dioxin receptor ahr is a ligand. The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the toxicity and tumourpromoting properties of. Aryl hydrocarbon receptor ahr agonists suppress interleukin.
The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. Thatcher th, williams ma, pollock sj, mccarthy ce, lacy sh, phipps rp, sime pj. Role of the aryl hydrocarbon receptor in sugen 5416induced. Nov 17, 2016 the aryl hydrocarbon receptor is an evolutionarily conserved receptor recognizing environmental compounds, including a number of ligands produced directly and indirectly by the microbiome. In addition to binding to pollution and endogenous ligands, the ahr binds to. For both men and women, colorectal cancer crc is the second leading cause of cancer death in the united states, primarily as a consequence of limited therapies for metastatic disease. Accumulating experimental evidence has identified numerous endogenous ligands regulating the ahr in a variety of physiological and pathological conditions, including atherothrombosis 5 and cancer.
The hallmark of ahr activation is the upregulation of the cytochrome p450 enzymes that metabolize many of these toxic compounds. The aryl hydrocarbon receptor ahr was discovered in the late 1970s as a. Subsequent studies showed that ahrmediated transcription was dependent on formation of a nuclear heterodimer composed of the. Here, we show that ahr is highly induced in b cells. The ahr influences the major stages of tumorigenesis initiation, promotion, progression, and. The aryl hydrocarbon receptor ahr belongs to the basic helixloophelix perarntsim homology domain family. After 16 h of treatment with bnf 5 m, sga360 10 m, or sga315 10 m in media containing delipidated serum, mrna levels of indicated genes were examined by qrtpcr analysis. Dietary flavonoid naringenin induces regulatory t cells. Metabolites in a mouse cancer model enhance venous. Abstract the aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor ahr.
Emerging evidence suggests that ahr is a key sensor allowing immune. Frontiers the aryl hydrocarbon receptor and tumor immunity. Evidence for new lightindependent pathways for generation. Kynurenic acid kyna is also an ahr ligand, converted from kyn by kynurenine aminotransferase kat. Ahr binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxinlike compounds. The aryl hydrocarbon receptor ahr was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8tetrachlorodibenzopdioxin tcdd and structurally related halogenated aromatics. We have demonstrated previously that a photoproduct of tryptophan, 6formylindolo3,2bcarbazole ficz, fulfills the criteria for an. Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function. Expression of ahr mrna a and protein b, and expression of cyp1a1 mrna c and protein d in whole lungs from male and female suhx rats and their normoxic littermates n 34 per group, repeated in triplicate are shown.
Aryl hydrocarbon receptor refubium freie universitat berlin. The aryl hydrocarbon dioxin receptor ahr has been studied for several decades largely because of its critical role in xenobiotic. The aryl hydrocarbon receptor ahr or ahr or ahr or ahr is a protein that in humans is encoded by the ahr gene. Cd56 bright and cd56 dim nk cells, which differ in maturation, function and distribution. This study aims to clarify its prognostic impact in breast cancer bc. The aryl hydrocarbon receptor ahr is a nuclear transcription factor known as a dioxin receptor and mediates the toxic effects of industrial contaminants. Studies on various tumor types and tumor cell lines have shown high ahr expression, suggesting that ahr is activated constitutively in. The aryl hydrocarbon receptor ahr is an important cytosolic, liganddependent transcription factor.
Request pdf the aryl hydrocarbon receptor in anticancer drug discovery. The aryl hydrocarbon receptor ahr is a ligandactivated. Abstract the aryl hydrocarbon receptor ahr is a ligand activated transcription factor that. May 15, 2017 the aryl hydrocarbon receptor ahr was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8tetrachlorodibenzopdioxin tcdd and structurally related halogenated aromatics. Dec 26, 2019 mostafa belghasem, daniel roth, sean richards, marc arthur napolene, joshua walker, wenqing yin, nkiruka arinze, chimera lyle, cheryl spencer, jean m. The ahr was discovered as the receptor that binds 2,3,7,8tetrachlorodibenzopdioxin tcdd. The aryl hydrocarbon receptor ahr is a liganddependent transcription factor with diverse functions in detoxification of xenobiotics, inflammatory responses, and tissue homeostasis. The prognostic impact of the aryl hydrocarbon receptor ahr.
The ahr was discovered as the receptor that binds 2,3,7,8tetrachlorodibenzopdioxin tcdd, dioxin with high affinity and is capable. Discovery of the aryl hydrocarbon receptor ahr was the result of several efforts to understand the mechanism by which polycyclic aromatic hydrocarbons induce their own metabolism via aryl hydrocarbon hydroxylase ahh activity now known to be mediated by cyp1a1. Natural tryptophan metabolitesmediated activation of. Using cyp1a1 mrna as an ahresponsive end point, we observed that the tryptophan metabolites were weak ahr.
Induction of this apoptosis signal in stromal cells is dependent on activation of the aryl hydrocarbon receptor ahr, a cytosolic receptor that is converted into a transcription factor on binding of any one of a number of pahs, halogenated aromatic hydrocarbons hahs, or planar polychlorinated biphenyls pcbs 3537. The aryl hydrocarbon receptor ligand omeprazole inhibits. The aryl hydrocarbon receptor ahr is a highly conserved liganddependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses summary by mouraalves et al. Evidence for new lightindependent pathways for generation of. As the known number of ahrmediated processes grows, so too does the importance of determining what endogenous ahr ligands are produced, how their production is regulated, and what biologic consequences ensue. The aryl hydrocarbon receptor in anticancer drug discovery. The tryptophan microbiota metabolites indole3acetate, indole3aldehyde, indole, and tryptamine are aryl hydrocarbon receptor ahr ligands, and in this study we investigated their ahr agonist and antagonist activities in nontransformed young adult mouse colonocyte yamc cells. The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the toxicity and tumourpromoting properties of the carcinogen 2,3,7,8.
An aryl hydrocarbon receptormediated amplification loop. The aryl hydrocarbon receptor ahr is a ligandactivated transcrip tion factor. Binding of ligands such as polycyclic aromatic hydrocarbons to the aryl hydrocarbon receptor ahr and. Our laboratory has been actively investigating the role of the aryl hydrocarbon receptor ahr in the immune system, and the variable effects seen after binding endogenous and exogenous ligands. The aryl hydrocarbon receptor ahr has long been studied by toxicologists as a ligandactivated transcription factor that is activated by dioxin and other environmental pollutants such as polycyclic aromatic hydrocarbons pahs. Kynurenine signaling through the aryl hydrocarbon receptor. Owing to the evolutionary conservation of this gene and its widespread expression in the immune and circulatory systems, ahr has for many years been almost exclusively studied by the. The aryl hydrocarbon receptor modulates the function of. Hepatitis b virus xassociated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core. It is an important factor in immunity and tissue homeostasis, and structurally diverse compounds from the environment, diet, microbiome, and host metabolism can induce ahr activity. Owing, in part, to the ability of xenobiotic ligands to have persistent effects on the immune system in exptl. Dec 26, 2019 accumulating experimental evidence has identified numerous endogenous ligands regulating the ahr in a variety of physiological and pathological conditions, including atherothrombosis 5 and cancer. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous lowaffinity ligands for the aryl hydrocarbon receptor ahr, a cytosolic, ligandoperated transcription. The aryl hydrocarbon receptor ahr, a ligandinduced nuclear receptor transcription factor with a well characterized role as an environmental sensor for dioxins, was recently shown to regulate cellfate decisions during t cell differentiation quintana et al.
Correlation of the aryl hydrocarbon receptor with fshr in. Studies on various tumor types and tumor cell lines have shown high ahr expression, suggesting that ahr is activated constitutively in tumors and. The aryl hydrocarbon receptor ahr has long been studied by toxicologists as a. Role of the aryl hydrocarbon receptor in carcinogenesis and. Tryptophan trp metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Aryl hydrocarbon receptor ahr ligands as selective ahr. Towards targeting the aryl hydrocarbon receptor in cystic. Exposure to aryl hydrocarbon receptor ahr ligands attenuates mrna levels of fatty acid and cholesterol synthesis genes. Friend and foe the aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the.
Citeseerx document details isaac councill, lee giles, pradeep teregowda. Francis, cristal thompson, christopher andry, stephen a. The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that mediates many of the biological and toxic effects of halogenated aromatic hydrocarbons hahs, polycyclic aromatic hydrocarbons pahs, and other structurally diverse ligands. Impaired aryl hydrocarbon receptor ligand production by. The aryl hydrocarbon receptor ahr is a dna binding protein that acts as a nuclear receptor mediating xenobiotic metabolism and environmental responses. A constitutively active dioxinaryl hydrocarbon receptor. The aryl hydrocarbon receptor ahr is a ligand activated transcription factor that is best known for mediating the toxicity and tumor promoting properties of the. The aryl hydrocarbon receptor ahr binds structurally diverse ligands that vary from the environmental toxicant 2,3,7,8tetrachlorodibenzopdioxin tcdd to ahractive pharmaceuticals and healthpromoting phytochemicals. The aryl hydrocarbon receptor ahr is a ligand activated transcription factor that is best known for mediating the toxicity and tumor promoting properties of the carcinogen 2,3,7,8tetrachlorodibenzopdioxin, commonly referred to as dioxin. The aryl hydrocarbon receptor controls cellfate decisions. Ahr expression and subcellular location were then analyzed by. Over 30 years of research has uncovered additional roles for the ahr in xenobiotic metabolism and normal vascular development.
Binding of ligands such as polycyclic aromatic hydrocarbons to the. The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the toxicity and tumourpromoting properties of the. Activation of the aryl hydrocarbon receptor ahr, a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobioticfree conditions is of considerable scientific interest. Impaired aryl hydrocarbon receptor ligand production by the. Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl. Mechanisms regulating nk cell functions are not completely understood. Nov 24, 2014 the aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the toxicity and tumourpromoting properties of the carcinogen 2,3,7,8. Ah receptorinteracting protein aip also known as aryl hydrocarbon receptorinteracting protein, immunophilin homolog ara9, or hbv xassociated protein 2 xap2 is a protein that in humans is encoded by the aip gene. Activation of the ahr has long been known to cause immunotoxicity, including thymic involution. Certain cancers can escape immune recognition via ahr signaling pathways. The aryl hydrocarbon receptor, more than a xenobiotic. Ahr studies have mainly focused on understanding molecular basis of toxicity induced by the prototypical ahr ligand 2,3,7,8tetrachlorodibenzop. Dietary flavonoid naringenin induces regulatory t cells via.
Human natural killer nk cells are divided into two subsets. It dimerizes with arnt ahr nuclear transporter, leading to the regulation of target genes implicated in several diseases, including cancer. Aryl hydrocarbon receptor activity of tryptophan metabolites in. Aryl hydrocarbon receptor ahr is a ligandactivated transcriptional factor. The inhibition of lung cancer cell migration by ahrregulated. Supplementation with ahr agonist or a lactobacillus strain naturally producing ahr ligands improves both dietary and geneticinduced metabolic impairments. Persistent binding of ligands to the aryl hydrocarbon. Binding of ligands such as polycyclic aromatic hydrocarbons to the aryl hydrocarbon receptor ahr and the sequence of events leading to induction of xenobioticmetabolising enzymes such as the cytochrome p450 isoform 1a1 and subsequent generation of dna adducts is historically associated with the process of chemical carcinogenesis. The aryl hydrocarbon receptor ahr is a cytoplasmic receptor and transcription factor activated through cognate ligand binding.
Mostafa belghasem, daniel roth, sean richards, marc arthur napolene, joshua walker, wenqing yin, nkiruka arinze, chimera lyle, cheryl spencer, jean m. The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that was first discovered as an intracellular protein that bound with high affinity to the environmental toxicant 2,3,7,8tetrachlorodibenzopdioxin tcdd. Patients with chronic kidney disease ckd are exposed to uremic toxins and have an increased risk of cardiovascular disease. Using cyp1a1 mrna as an ahresponsive end point, we observed that the tryptophan. Increasing evidence implicates the aryl hydrocarbon receptor ahr as a possible regulator of mammary carcinogenesis. Study of this receptor traditionally was in the domain of toxicologists, as it was originally defined as a receptor to 2,3,7,8tetrachlorodibenzo p. Kynurenine kyn is converted from tryptophan in host metabolism.
The aryl hydrocarbon receptor ahr was initially discovered as the intracellular protein that mediated the toxic effects of 2,3,7,8tetrachlorodibenzopdioxin tcdd and structurallyrelated halogenated aromatic has compounds including halogenated dibenzopdioxins, dibenzofurans and polychlorinated biphenyls pcbs 1, 2, 3. Role of the aryl hydrocarbon receptor in sugen 5416. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the ahr. Expression of aryl hydrocarbon receptor ahr and cyp1a1 in lung tissue from the sugenhypoxic suhx animal model. The aryl hydrocarbon receptor is a member of the family of basic helixloophelix transcription factors. There are three groups for microbiotamediated ahr ligands.
A constitutively active dioxinaryl hydrocarbon receptor induces stomach tumors. The aryl hydrocarbon receptor ahr is a protein best known for its role in mediating toxicity. The aryl hydrocarbon receptor modulates the function of human. Aryl hydrocarbon receptor activity of tryptophan metabolites. Role of the aryl hydrocarbon receptorarntcytochrome p450. The prognostic impact of the aryl hydrocarbon receptor. Aryl hydrocarbon receptor is activated in patients and. Role of the aryl hydrocarbon receptor in carcinogenesis. Emerging evidence suggests the promoting role of the ahr in the initiation, promotion, progression, invasion, and metastasis of cancer cells. Jun 25, 2019 kynurenine, a tryptophan metabolite generated by the enzyme ido1, is a ligand for the aryl hydrocarbon receptor ahr. Albeit this is a major issue in basic and clinical research, an increasing number of investigators are turning their efforts to try to understand the physiology of the ahr. In addition, variations in the inducibility of ahh between mouse strains, as well as mutations present in.
The aryl hydrocarbon receptor ahr is a ligandactivated transcription factor that is best known for mediating the toxicity and tumourpromoting properties of the carcinogen 2,3,7,8tetrachlorodibenzopdioxin, commonly referred to as dioxin. Canonical and noncanonical aryl hydrocarbon receptor. The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis. There are remarkable differences in the toxicity of tcdd and related halogenated aromatics has vs. Aryl hydrocarbon receptor as a new therapeutic target for. Here we investigated ahr activation in patients with ckd and in a murine model of. Role of the aryl hydrocarbon receptor in colon neoplasia. Kynurenine, a tryptophan metabolite generated by the enzyme ido1, is a ligand for the aryl hydrocarbon receptor ahr. In addition, there are some examples in human cancer where the tumors. The aryl hydrocarbon receptor ahr is a member of the basic helixloophelixper arntsim bhlhpas subgroup of the bhlh superfamily of transcription factors and is the only member of this family known to be activated by ligands 1. In addition, ahr has been implicated in multiple cellular processes and its expression has been shown to play a critical role in tumorigenesis, including human oral cancer cell lines. The aryl hydrocarbon receptor is a tumor suppressorlike gene in. Ahr is a transcription factor which is activated by ligands such as dioxin and translocates from the cytoplasm to the nucleus. Metaanalyses performed at the mrna level demonstrated that the predictive value of ahr expression in bc depends on the lymph node ln status.
Request pdf aryl hydrocarbon receptor ligands in cancer. These toxins induce a vascular procoagulant phenotype. Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptortissue factor axis. Since its discovery in the 1980s, the aryl hydrocarbon receptor ahr has been a major focus in toxicology due to the fact that it mediates the effects of the halogenated aromatic hydrocarbon environmental pollutants. The endogenous ligandactivated aryl hydrocarbon receptor ahr plays an important role in numerous biologic processes.