Abstract
The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.
Highlights
Human exposure to dioxins and dioxin-like compounds has been associated with a range of toxic effects including human carcinogenicity at multiple sites in occupational settings
To address the tumor-suppressive action of aryl hydrocarbon receptor repressor (AhRR) in vivo, we used a syngeneic murine tumor model to assess changes in tumor susceptibility associated with inflammation
AhRR Tg mice compared to wt B6 mice with or without TCDD treatment (Figure 1)
Summary
Human exposure to dioxins and dioxin-like compounds has been associated with a range of toxic effects including human carcinogenicity at multiple sites in occupational settings. It has been previously shown that they mediate their toxicity through activation of the aryl hydrocarbon receptor (AhR) [1]. Exposure to dioxin and dioxin-like compounds has been shown to be carcinogenic and especially associated with the development of non-Hodgkin lymphoma (NHL). AhR activation via endogenous ligands can represent a critical event in human carcinogenesis and can result in the development of immune tolerance and increased survival of cancer cells [7]. The mechanisms of TCDD-mediated toxicity and AhR-dependent tumor promoting activity have been investigated in numerous studies with a focus on TCDD’s action as a potent hepatic tumor promoter [2,8].
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