ONCOLOGY LETTERS 21: 460, 2021 Role of aryl hydrocarbon receptor in central nervous system tumors: Biological and therapeutic implications (Review) MONTSERRAT ZARAGOZA‑OJEDA1,2, ELISA APATIGA‑VEGA1 and FRANCISCO ARENAS‑HUERTERO1 1Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Mexico City 06720; 2Posgrado en Ciencias Biológicas, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, México Received January 28, 2020; Accepted January 25, 2021 DOI: 10.3892/ol.2021.12721 Abstract. Aryl hydrocarbon receptor (AHR) is a ligand‑ 6. Non‑canonical AhR pathway activated transcription factor, whose canonical pathway 7. Potential therapeutic applications of the crosstalk between mainly regulates the genes involved in xenobiotic metabolism. AhR pathway and central nervous system tumors However, it can also regulate several responses in a non‑ 8. Conclusions canonical manner, such as proliferation, differentiation, cell death and cell adhesion. AhR plays an important role in central nervous system tumors, as it can regulate several 1. Background of AhR research cellular responses via different pathways. The polymorphisms of the AHR gene have been associated with the development of The study of AhR can be discussed from two standpoints; the gliomas. In addition, the metabolism of tumor cells promotes first one reflects the reality of current times, that is, human tumor growth, particularly in tryptophan synthesis, where exposure to synthetic organic compounds and the conse‑ some metabolites, such as kynurenine, can activate the AhR quences that has on human health. During the 1970s, the pathway, triggering cell proliferation in astrocytomas, medul‑ studies of several toxicologists, biochemists and molecular loblastomas and glioblastomas. Furthermore, as part of the biologists focused on the toxic effects of 2,3,7,8‑tetrachlorod‑ changes in neuroblastomas, AHR is able to downregulate ibenzo‑p‑dioxin (TCDD), a polychlorinated dibenzo‑p‑dioxin the expression of proto‑oncogene c‑Myc, induce differentia‑ that was identified as an unintentional by‑product of the tion in tumor cells, and cause cell cycle arrest and apoptosis. herbicide 2,4,5‑trichlorophenoxyacetic acid synthesis (1). Collectively, these data suggested that the modulation of the Individuals who worked in the manufacturing of this AhR pathway may downregulate tumor growth, providing herbicide suffered diseases such as porphyria cutanea tarda a novel strategy for applications for the treatment of certain and chloracne (2). It was proven by a later study that TCDD tumors through the control of the AhR pathway. exposure was the cause of porphyria in such workers, which acted by increasing the activity of the initial enzyme in heme biosynthesis, δ‑aminolevulinic acid synthetase (3). Contents The second standpoint is the rather accidental finding of certain studies from the early 1950s showing that tumor 1. Background of AhR research development was inhibited in rats exposed to the carcinogen 2. A glance at AHR molecular features 3‑methylcholanthrene (3‑MC) when it was administrated simul‑ 3. AHR‑associated proteins taneously with other carcinogens (4). It was later proven that this 4. Canonical AhR pathway inhibition of carcinogenesis can be induced not only by 3‑MC, 5. Direct interactions between AHR and other proteins but also by a great variety of polycyclic aromatic hydrocarbons (PAH), as these compounds impede the action of an enzyme that modifies carcinogens, nowadays known as cytochrome P450 family 1 subfamily A member 1 (CYP1A1), a member of the cytochrome P450 family (5). Later, in 1969, that modifying Correspondence to: Dr Francisco Arenas‑Huertero, Laboratorio activity was named Ah hydroxylase (AHH) and certain studies de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, 162 Calle Dr. Márquez, Colonia Doctores, revealed that in some, but not all, syngeneic strains of mice, this Mexico City 06720, México enzyme activity was induced by PAHs (6,7), which suggested E‑mail: [email protected] the existence of a gene that controls AHH activity, termed the Ah locus (8,9). The Ah locus was then found to be involved in the Key words: brain tumors, astrocytoma, medulloblastoma, regulation of carcinogenicity, mutagenicity and toxic responses neuroblastoma, aryl hydrocarbon receptor to PAHs (10). This created an opportunity to examine other types of toxic compounds, such as TCDD and 3‑MC; the results showed that TCDD was 30,000 times more potent in inducing 2 ZARAGOZA‑OJEDA et al: ROLE OF AhR IN CNS TUMORS: BIOLOGY AND THERAPEUTICS AHH activity than 3‑MC (11). Therefore, TCDD became the IL‑13, and growth factors such as transforming growth factor‑β ideal molecule for testing the activity of the Ah locus (12). (TGF‑β) (25). The AHR promoter also possesses motifs to bind The study of steroid receptors was also increasing at the time; T‑cell factor/lymphoid enhancer‑binding factor (TCF/LEF), with this in mind, the idea of a ‘receptor’ that controls the Ah locus factors that are involved in the Wnt pathway by interacting emerged, which may also explain the greater affinity for certain with β‑catenin (26). Finally, the AHR promoter was also found compounds, such as TCDD, over others, such as 3‑MCA (13). The to have 11 cis nuclear receptor binding sites, which include first radioactively labeled TCDD [(3H)TCDD)] was synthetized, progesterone, androgen, glucocorticoid, proliferation‑activated and finally the existence of a receptor was confirmed in 1979 peroxisome, farsenoid X and the vitamin D receptors. The and the term AHR was used for the first time (14). Unexpectedly, existence of a complete list of the AHR promoter characteristics only a fraction of (3H)TCDD bound to the receptor in the cyto‑ enabled the understanding of the dual activity of AHR, with the plasm as expected, but another portion bound to the receptor in constitutive one being associated with embryogenesis and fetal the nucleus, as described for the steroid receptors. Shortly after development when the receptor activity is particularly critical, AHR discovery, it was determined that the weight of the receptor and the second with specific tissue expression (27). varied depending on its origin; when it was isolated from the All these characteristics are conserved among the human cytoplasm it was heavier than when found in the nucleus (15,16). and murine AHR sequences, with the main difference between This fact aroused interest regarding other proteins associated them being the mRNA length, which is longer in humans with the receptor, and their role in its function. A few years later, (~6.6 kb) than in mice (5.0‑5.4 kb). The open reading frame has a protein was discovered that formed a dimer with AHR in the 11 exons, organized to form a mature mRNA, with 28 domains nucleus, which was named the AHR nuclear receptor translo‑ in humans and 26 in mice (28). Focusing on the AHR domains, cator (ARNT) (17). Finally, it was confirmed that the formation this receptor is a member of the basic Helix‑Loop‑Helix of the TCDD‑AHR‑ARNT complex was indispensable for the (bHLH) superfamily of transcriptional regulators. The induction of AHH activity (18). In 1986, a nucleotide sequence, members of this family are involved in critical developmental 5'‑TNGCGTG‑3', to which the TCDD‑AHR‑ARNT complex processes, including sex determination and the development of bound to induce the AHH activity, was identified and named the nervous system and muscles. Like other members of this dioxin response element (19). Subsequently, in Japan, studies superfamily of proteins, it contains a binding region to DNA at were conducted using other xenobiotic compounds. These the amino‑terminal end and an additional Per‑Arnt‑Sim (PAS) studies found that the xenobiotic‑AHR‑ARNT complex bound domain at the carboxy‑terminal (29,30). The region of the basic to the same sequence reported before, which was then renamed residues is important for the interaction of AHR with the cis xenobiotic response elements (XRE); today it is also known as sequence of the XRE, while the bHLH motif is important for Ah response elements, a term used less often due to its simi‑ the heterodimerization between AHR and ARNT (31,32). larity to the antioxidant response elements (AREs) (20,21). From that moment forward, the expression of CYP1A1 in response 3. AHR‑associated proteins to natural compounds, drugs and other xenobiotics in general, has been used as an indirect evaluation of the participation of AHR research was initially based only on its exposure to or AHR, and therefore xenobiotic metabolism. However, it was interaction with TCDD, but the molecular structure of the AHR subsequently recognized that these XRE sequences were found protein was unknown. In the cytosolic fraction, AHR exhib‑ in a large number of gene promoters, and not only in CYP1A1. ited a higher sedimentation value, which upon the addition of Nowadays, it is known that the function of AHR extends far TCDD, was found to be decreased and located instead in the beyond xenobiotic metabolism; it actually functions as a master nuclear fraction (33). This finding revealed the existence of two regulator to control several biological processes, including cell different forms of the receptor, depending on cellular localiza‑ proliferation, adhesion, differentiation and death, potentially tion. It was shown electrophoretically in subsequent studies among others not yet known (22). that this weight difference was due to the fact that the cyto‑ plasm receptor was found in a protein complex that included 2. A glance at AHR molecular features 2 isoforms of mouse heat shock protein of 90 kDa (Hsp90) and an X‑associated protein 2, also known as AHR‑interacting In 1994, the human AHR promoter was cloned, and its main protein (AIP) or AHR‑associated protein 9 (ARA9) (34‑36). characteristics were described. First, this promoter was not found The proteins in this complex are important for the function of to contain a TATA box; instead, several binding motifs were the AHR.