A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

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.

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development

“…The results suggest that AhRR overexpression in the host environment is sufficient to inhibit orthotopic growth of mammary tumor cells. This builds on our prior study in which we demonstrated that growth of lymphoma cells was suppressed in AhRR Tg mice (42). We note that the growth of E0771 cells was suppressed in untreated AhRR transgenic mice suggesting that AhRR overexpression in the host may suppress tumor growth independent of exogenous and toxic AhR ligands.…”

“…The results are in line with the in vivo findings and confirm previous reports showing a reduced cell proliferation, increased apoptosis and inhibition of inflammatory invasion and migration of breast cancer cells by AhRR overexpression ( 1 , 8 , 17 , 37 ). Our previous studies found that C/EBPβ and COX-2 are important mediators of an AhR-dependent and TCDD-induced resistance to apoptosis in lymphoma cells, demonstrating their critical role in AhR-driven tumor cell survival ( 42 , 51 ). In addition to a host-dependent tumor suppressive effect of AhRR indicated by current data from a mouse xenograft model, the results with mammary tumor cells suggest that AhRR mediates also cell-intrinsic responses associated with the suppression of C/EBPβ and COX-2.…”

A New Insight into the Potential Role of Tryptophan-Derived AhR Ligands in Skin Physiological and Pathological Processes

“…Although AHR expression levels do not differ significantly in various types of skin cancer ( Figure 3 A), we observed a significant downregulation of AHRR expression in skin cutaneous melanoma (SKCN) ( Figure 3 B). Vogel et al report that the upregulated AhRR expression inhibits the AhR-mediated antiapoptotic response in mouse embryonic fibroblasts [ 206 ]. As AhRR tends to play a significant role in suppressing inflammation, the downregulated AHRR expression may promote tumor growth.…”

Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor

“…Thus, the AhRR is an AhR competitor in that it may form the heterodimeric AhRR/ARNT complex, which binds to the XRE, and consequently repress the transcription. The AhRR effects mediate key processes such as inflammation and tumor growth that have led to its consideration as a drug target [ 47 , 48 ]. The repression pathway is also controlled by the receptor itself and its transcriptional outcomes forming a regulatory circuit [ 49 ].…”