How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

Abstract

For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.

Loss of Aryl Hydrocarbon Receptor Favors K-RasG12D-Driven Non-Small Cell Lung Cancer

“…The aryl hydrocarbon receptor (Ahr) is a transcription factor with known roles in tumor progression and dissemination in different tissues and organs [17][18][19][20]. Previous work has revealed that Ahr affects tumor development and spreading in a cell and tissuetype dependent manner.…”

Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis

“…Through comprehensive analysis, it was revealed that ARNT and TBP have consistently poor effects on PFS and OS. AHR, a ligand-activated transcription factor, is notable for its role in environmental chemical toxicity [ 92 , 93 , 94 ]; however, in recent studies, AHR was also recognized to play a critical role in tumorigenesis through complex epigenetic and pathogenetic mechanisms encompassing both pro- and anti-tumorigenic activities [ 95 , 96 ]. AHR exists in the cytoplasm and is induced and activated by linking with a group of environmental pollutants as well as other AHR ligands from microbes and diet, and it undergoes certain conformational transformations together with SRC and other cofactors in the cytoplasm to translocate to the nucleus in a dissociated form [ 95 , 97 , 98 , 99 ].…”

“…AHR, a ligand-activated transcription factor, is notable for its role in environmental chemical toxicity [ 92 , 93 , 94 ]; however, in recent studies, AHR was also recognized to play a critical role in tumorigenesis through complex epigenetic and pathogenetic mechanisms encompassing both pro- and anti-tumorigenic activities [ 95 , 96 ]. AHR exists in the cytoplasm and is induced and activated by linking with a group of environmental pollutants as well as other AHR ligands from microbes and diet, and it undergoes certain conformational transformations together with SRC and other cofactors in the cytoplasm to translocate to the nucleus in a dissociated form [ 95 , 97 , 98 , 99 ]. AHR can heterodimerize with ARNT, a nuclear translocator, to compose the AhR-ARNT complex, which subsequently binds with specific DNA sequences and xenobiotic response element (XRE) in the enhancer region of certain genes associated with TBP, leading to transcriptional activation of enzymes, such as the cytochrome P450 (CYP) enzymes 1A1 (CYP1A1), CYP1A2, and CYP1B1, for xenobiotic metabolism to induce carcinogenicity of cancer stem cells as tumors or initiate cancer ( Figure 5 ) [ 100 , 101 , 102 , 103 ].…”

“…AHR can heterodimerize with ARNT, a nuclear translocator, to compose the AhR-ARNT complex, which subsequently binds with specific DNA sequences and xenobiotic response element (XRE) in the enhancer region of certain genes associated with TBP, leading to transcriptional activation of enzymes, such as the cytochrome P450 (CYP) enzymes 1A1 (CYP1A1), CYP1A2, and CYP1B1, for xenobiotic metabolism to induce carcinogenicity of cancer stem cells as tumors or initiate cancer ( Figure 5 ) [ 100 , 101 , 102 , 103 ]. Although the current research on the AHR binding pathway and serous ovarian tumors is still limited, it can be roughly understood that the AHR binding pathway influences the formation and occurrence of serous ovarian malignancy through the deep deletion and amplification of AHR transcription factors [ 95 , 96 , 104 , 105 ]. Moreover, localization of AHR in the nucleus of tumor cells has been associated with a worse outcome in patients with ovarian cancer, and the role of the AHR/ARNT/CYP-enzyme pathway [ 106 , 107 ] and AHR-driven TBP gene expression in carcinogenesis and cancer initiation, as well as its potential use, have been considered as therapeutic targets for better outcomes [ 108 ].…”

Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

“…Studies on various tumor types and tumor cell lines have shown high AhR expression, suggesting that AhR is activated constitutively by specific ligands in tumors and facilitates their growth or immune evasion [ 13 ]. Specifically, in tumor cells, emerging evidence suggests a promoting role for AhR in the initiation, promotion, progression, invasion, and metastasis of cancer cells [ 1 , 5 , 14 , 15 ].…”