Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines

Abstract

There is increasing evidence that the aryl hydrocarbon receptor (AHR) plays a role in tumor progression through numerous mechanisms. We have previously shown that, in certain cancer cell lines that are typically non-responsive to cytokine-mediated IL6 induction, activation of the AHR with the agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin derepresses the IL6 promoter and allows for synergistic induction following IL1β treatment. The mechanism by which this occurs involves liganded AHR binding upstream from the transcription start site and dismissing HDAC-containing corepressor complexes, giving rise to a promoter structure that is more amenable to NF-κB activation. This fact, combined with observations of multiple endogenously-produced chemicals activating the AHR, led us to study its role in basal expression among high cytokine-producing cancer cell lines. The current study provides evidence that several head and neck squamous cell carcinoma cell lines have a level of constitutively bound AHR at the IL6 promoter, allowing for higher basal and readily inducible IL6 transcription. Treatment of these cell lines with an AHR antagonist led to dismissal of the AHR from the IL6 promoter and recruitment of corepressor complexes, thus diminishing cytokine expression. Head and neck squamous cell carcinoma is typically a high cytokine-producing tumor type, with IL6 expression levels correlating with disease aggressiveness. For this reason, AHR antagonist treatment could represent a novel adjuvant therapy for patients, lowering pro-growth and anti-apoptotic signaling with minimal systemic side effects.

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

“…The AHR is a ligand-activated receptor that not only plays a role in mediating the toxicity of TCDD and related compounds but is also a potential target for the treatment of several diseases including autoimmune diseases, various inflammatory conditions, and cancer (McDougal et al, 2001;Quintana et al, 2008Quintana et al, , 2010Zhang et al, 2009Zhang et al, , 2012DiNatale et al, 2010bDiNatale et al, , 2011Murray et al, 2010;O'Donnell et al, 2010;Kiss et al, 2011;Li et al, 2011;Opitz et al, 2011;Singh et al, 2011). Depending on the tissue or cell, AHR agonists or antagonists may be required, and there is also evidence that the effects of various AHR-active compounds are structure-dependent.…”

Aryl Hydrocarbon Receptor Antagonism Attenuates Growth Factor Expression, Proliferation, and Migration in Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

“…RNA isolation and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed as previously described (DiNatale et al, 2011).…”

“…These studies also established that nuclear translocation of AHR results in binding of the AHR-ARNT heterodimerized complex to multiple imperfect DREs present within the IL1B and IL6 genes, thus regulating transcriptional activation . Furthermore, we have determined that constitutive AHR activity in head and neck squamous cell carcinomas (HNSCCs) contributes to their highly invasive and migratory phenotype (DiNatale et al, 2011). Our previous studies also indicate that the AHR antagonist CH223191 inhibits growth factor expression in OSC19 and HNSCC30 cell lines in an AHR-dependent manner .…”

“…Other possible therapeutic activities attributed to AHR antagonists include SR1, a potent AHR antagonist used in hematopoietic stem cell expansion ex vivo, and the AHR antagonist 6,29,49-trimethoxyflavone, which inhibits expression of IL6 in multiple HNSCC cell lines in the presence of inflammatory signaling. These examples suggest that AHR antagonists exhibit therapeutic potential for the treatment of a variety of diseases (Boitano et al, 2010;DiNatale et al, 2011).…”

Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes

“…However, Ahr can modulate RelB and RelA to induce or inhibit gene expression, respectively (11)(12)(13). Furthermore, cell density is a critical determinant of PAH effects, as noted in rabbit osteoclast cultures (14).…”