Journal Article

Aryl hydrocarbon receptor ligands in cancer: friend and foe

Patterson, Andrew D., Perdew, Gary H., Murray, Iain A.

2014

Overview

Key Points The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD; commonly referred to as 'dioxin'). Three distinct classes of ligands bind to AHR: agonists, antagonists and selective AHR modulators. AHR is activated by endogenous ligands such as kynurenine, kynurenic acid and indoxyl sulphate, and physiologically relevant flora can produce potent AHR ligands from tryptophan. Human AHR and mouse AHR exhibit substantial differences in ligand specificity, which might influence the progression of cancer. This complicates the validity of mouse models for studying the effects of AHR on human carcinogenesis. Numerous studies demonstrate the ability of AHR to increase the proliferative and migratory potential of tumour cells. AHR directly modulates inflammatory signalling, and AHR levels are often increased in tumours, probably as a result of inflammatory signalling. AHR agonist-mediated activity can have a key role in the production of regulatory T cells and thus could have a role in immune tolerance in cancer. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of dioxin. AHR levels are increased with constitutive nuclear localization in many tumours. How might AHR facilitate tumour progression, and can it be therapeutically modulated? 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/327 / 631/67/580 / 631/80/86/388 / Adaptive Immunity / Animals / Biomedicine / Cancer / Cancer Research / Care and treatment / Cell Proliferation / Cell receptors / Humans / Immunity, Innate / Ligands / Ligands (Biochemistry) / Neoplasm Metastasis / Neoplasms - etiology / Neoplasms - immunology / Properties / Receptors, Aryl Hydrocarbon - agonists / Receptors, Aryl Hydrocarbon - physiology / review-article