Abstract
Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of ‘stemness’ genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including α-ketoglutarate, and treatment of cancer cells with α-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKα directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance.
Highlights
The aryl hydrocarbon receptor (AhR), a ligand-operated transcription factor, is a xenosensor traditionally associated with xenobiotic metabolism[1]
AhR influences the major stages of tumorigenesis, and studies of aggressive tumors and tumor cell lines have shown increased levels of AhR protein and constitutive nuclear
We observed that both A549-ionizing radiation resistant (IR) and HK1-IR cells exhibited more stem-like properties, such as the capacity of sphere growth (Fig. 1b) and aldefluor assay in ALDH activity (Fig. 1c), compared to P cells
Summary
The aryl hydrocarbon receptor (AhR), a ligand-operated transcription factor, is a xenosensor traditionally associated with xenobiotic metabolism[1]. AhR facilitates tumor progression, disease tolerance defense, intestinal immunity, and B-cell proliferation[2,3,4,5]. The activation of nuclear factor (NF)-κB leads to a protumorigenic inflammatory microenvironment, and the IκB-kinase (IKK) complex, which consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ, tightly regulates the NF-κB pathway[8,9]. In most malignancies, the classical IKKβ/IKKγ-dependent NF-κB activation controls key functions for tumor initiation, promotion, and progression in tumors[10]. The role of IKKα is more complex in noncanonical NF-κB pathway[11,12]. Depending on the type of malignancy, IKKα can provide both tumor-promoting and tumor-suppressive mechanisms that are in most instances cell autonomous[13]
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