The role of the aryl hydrocarbon receptor in tumor cell phenotype
Open Access
- Author:
- DiNatale, Brett C
- Graduate Program:
- Molecular Medicine
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 29, 2010
- Committee Members:
- Gary H Perdew, Dissertation Advisor/Co-Advisor
Gary H Perdew, Committee Chair/Co-Chair
Jeffrey Maurice Peters, Committee Member
Craig Richard Baumrucker, Committee Member
Andrea Marie Mastro, Committee Member
Kumble Sandeep Prabhu, Committee Member - Keywords:
- ahr
aryl hydrocarbon receptor
cancer - Abstract:
- The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor widely associated with its function in xenobiotic metabolism and its ability to bind environmental pollutants in the polycyclic aromatic hydrocarbon family such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Upon ligand binding, the AHR translocates to the nucleus, exchanges its chaperone complex for its heterodimerization partner, the aryl hydrocarbon receptor nuclear translocator, and binds to dioxin response elements (DREs) in the promoter of target genes, driving transcription. However, researchers have tied the AHR to a variety of cellular processes in addition to xenobiotic metabolism, not all of which occur through DRE binding and direct transcriptional activation. The studies presented here build upon the finding that combinatorial treatment with exogenous AHR ligands and IL1B leads to synergistic IL6 expression in some typically non-responsive tumor cell lines. The overall hypothesis was that the AHR plays a molecular role in IL6 transcription and represents a viable point of treatment to mediate tumor cell signaling. Analysis of the mechanism by which these two signals mediate IL6 induction revealed that the liganded AHR binds to DREs far upstream from the IL6 promoter, yet plays a role in the de-repression of the chromatin of the proximal promoter through dismissal of co-repressor complexes. Following this, IL1B-induced NFkB activity is able to positively affect transcription of the IL6 gene. Subsequently, the role played by the AHR in the relatively high basal and readily inducible cytokine expression of head and neck squamous cell carcinoma (HNSCC) cell lines was assessed. Multiple HNSCC cell lines derived from various loco-regional tumors showed a similar state of IL6 de-repression with AHR occupancy of the promoter in the absence of exogenous ligand. This promoter configuration could be reversed and transcription repressed through treatment of cells with an AHR antagonist and the resultant decrease in receptor occupancy of the IL6 promoter. Next, the hypothesis was tested that basal AHR occupancy of the IL6 promoter in HNSCC cell lines is indicative of a constitutive level of receptor activity, and that the role of the AHR in various cellular processes that enhance tumor cell phenotype were similarly occurring. Treatment of HNSCC cell lines with AHR antagonists decreased tumor cell proliferation, migration, invasive ability, and prevented the increase of an integral protein for a chemotherapy efflux pump. The significance of the results presented in these studies reflects on both the field of AHR biology and the potential for AHR-targeted treatment in cancer, including HNSCC. Uncovering a mechanism whereby AHR activation is one of two signals required for gene regulation opens a new field of research into combinatorial effects of the receptor and points to previously undocumented genes as being AHR targets with or without DREs in the proximal promoter. Finally, AHR antagonist treatment is a viable method to counter constitutive AHR activity in some tumor cell types and diminishes their aggressive phenotype.