Role of aryl hydrocarbon receptor in central nervous system tumors: Biological and therapeutic implications

Abstract

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, whose canonical pathway mainly regulates the genes involved in xenobiotic metabolism. However, it can also regulate several responses in a non-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 cellular responses via different pathways. The polymorphisms of the AHR gene have been associated with the development of gliomas. In addition, the metabolism of tumor cells promotes tumor growth, particularly in tryptophan synthesis, where some metabolites, such as kynurenine, can activate the AhR pathway, triggering cell proliferation in astrocytomas, medulloblastomas and glioblastomas. Furthermore, as part of the changes in neuroblastomas, AHR is able to downregulate the expression of proto-oncogene c-Myc, induce differentiation in tumor cells, and cause cell cycle arrest and apoptosis. Collectively, these data suggested that the modulation of the AhR pathway may downregulate tumor growth, providing a novel strategy for applications for the treatment of certain tumors through the control of the AhR pathway.

Keywords: aryl hydrocarbon receptor; astrocytoma; brain tumors; medulloblastoma; neuroblastoma.

Figure 1.

Canonical activation of the AhR pathway. In the cytoplasm, AHR resides in a molecular complex, to give it stability (A); this complex is formed with two Hsp90 proteins, AIP and p23. Following ligand binding, AHR dissociates from the complex and translocates to the nucleus (B). Inside the nucleus, AHR dimerizes with ARNT (green arrows) to form a heterodimer that binds to the XRE sites on the gene promoters involved in xenobiotic metabolism (C). Following the activation of response genes, AHR becomes the target of the ubiquitin 3-ligase (D) and undergoes degradation by the 26S proteasome in the nucleus (E). The activation of the non-canonical pathway (orange arrows) is performed through the binding of AHR to other proteins, such as pRB, RelA or RelB. In this case, AHR and RelB together bind to other genes with an XRE cis site in their promoter, and activate several genes that participate in growth, differentiation, metabolism, the cell cycle, cell adhesion, apoptosis, immune response and inflammation (F). AHR, aryl hydrocarbon receptor; Hsp90, heat shock protein 90; AIP, AHR-interacting protein; ARNT, AHR nuclear receptor translocator; XRE, xenobiotic response elements; pRB, retinoblastoma.

Figure 2.

In astrocytoma and glioblastoma, the activation of the AhR pathway increases the expression of several genes, such as VEGF and TGF-β1 (green arrows) that are involved in angiogenesis and proliferation processes. In addition, the overexpression of Sp1 activates the transcription of AHR, increasing its protein levels. Moreover, there are AHR ligands, such as tryptophan metabolites, produced by the kynurenine pathway in central nervous system tumors such as astrocytoma (green arrows), which also bind and activate the AhR pathway. The strategies used to control the growth of neoplastic cells in astrocytoma and glioblastoma (red arrows) mainly involve the use of AHR antagonist. Another target for therapy is the use of complex-associated protein inhibitors to induce the instability of the receptor. An example of this is NVP-AUY922, which inhibits Hsp90 and induces AHR degradation. Another example is the use of inhibitors such as mithramycin A and AS1517499, which control the autoinduction of AHR protein expression and stop reactive responses. AHR, aryl hydrocarbon receptor; VEGF, vascular endothelial growth factor A; TGF-β1, transforming growth factor-β; Hsp90, heat shock protein 90; Sp1, specificity protein 1; TCF1/LEF1, T-cell factor/lymphoid enhancer-binding factor; AIP, AHR-interacting protein; IL, interleukin.

Figure 3.

Increased expression of c-Myc is the main characteristic of medulloblastomas, and could be a result of the overexpression of AHR, a transcriptional activator (blue arrows). This, in turn, induces an increase in Hes1 gene expression and causes proliferation (green arrows). Another aspect is the activation of several genes due to the action of AHR/RelB, including those responsible for IL-6 secretion and inflammation. Data have suggested that the best therapeutic strategy is to antagonize the AhR pathway (orange arrow). AHR, aryl hydrocarbon receptor; IL, interleukin.