Role of the aryl hydrocarbon receptor in ultraviolet-B radiation-induced DNA damage responses and skin carcinogenesis

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Absorbance of ultraviolet B (UVB) radiation by the DNA of epidermal cells results in the formation of mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPD), which critically contribute to skin carcinogenesis. The most important protective mechanisms against the genotoxic effects of UVB radiation are nucleotide excision repair (NER) and apoptosis.In the initial grant, we identified the aryl hydrocarbon receptor (AHR), a ligand-activated and UVB-sensitive transcription factor, to repress these early defense mechanisms, thereby critically contributing (approx. 50%) to photocarcinogenesis in mice. Whereas an inhibition of AHR led to accelerated CPD repair early after UVB exposure and enhanced apoptosis at later time points, treatment of UVB-irradiated keratinocytes with AHR agonists caused opposite effects.In the renewal proposal, we will assess the mechanism by which AHR influences NER activity. A thorough understanding of this process is important, in particular with regards to our previous results, showing that AHR agonists nearly completely inhibited the repair of UVB-induced CPDs. By conducting in vitro experiments as well as a carcinogenesis study with SKH-1 mice, we will test the hypothesis that exposure-relevant AHR agonists, such as polycyclic aromatic hydrocarbons, act co-carcinogenic by enforcing the development of UVB-initiated squamous cell carcinomas (SCC). The results of these studies are in particular of clinical relevance for individuals that are daily exposed to both stress factors and thus are at high risk for SCC development, such as roadmen and roofers. Further results from previous experiments provide evidence that AHR inhibition enhances the apoptosis susceptibility of SCC cells to genotoxic cytostatics. Hence, we will understand the molecular mechanisms by which AHR ligands facilitate the repair of lethal DNA double-strand breaks and thereby contribute to apoptosis resistance of SCC cells. Mechanistic in vitro studies and a mouse xenograft study will be conducted to test the hypothesis that a pharmacological inhibition of AHR in SCC cells increases the efficacy of co-applied genotoxic cytostatics. If this turns out to be true, it would open up new opportunities for the topical chemotherapy of SCC. Co-treatment with AHR antagonists would, for instance, allow to reduce the dose of side-effect-rich chemotherapeutics without affecting the clinical response. The proposed research project is of clinical relevance as it aims to characterize AHR-dependent processes in healthy skin exposed to genotoxic environmental factors, as well as in cytostatic-treated SCC. Hence, the results of this project are not only important for prevention but also for the therapy of cutaneous SCC.