Evidence suggests that estrogen affects the pulmonary response to carcinogenic pollutants such as dioxins. In this study, we examined dioxin and estrogen signaling crosstalk in lung adenocarcinoma cell lines that were engineered to exhibit different AhR/ERalpha phenotypes. Data showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) weakly antagonized estrogen-activated ERalpha activity in cells expressing abundant ERalpha but little AhR. Increase of AhR expression or presence of a dioxin responsive element (DRE) in proximity silenced the antiestrogenic effect of TCDD. AhR was bound to DRE and transcriptionally active in both TCDD-untreated and treated lung adenocarcinoma cells. 17beta-estradiol (E2) reduced basal and TCDD-induced AhR activity only in ERalpha-positive cells. AhR and ERalpha exhibited a protein-protein interaction in the presence of E2. Cotreatment with TCDD moderated this protein interaction. Colocalization of ERalpha and AhR at the estrogen responsive site under E2 and TCDD/E2 treatments implied that E2ERalpha might hijack AhR away from the dioxin responsive site. Increasing the relative expression of AhR to ERalpha counteracted inhibition of AhR activity by E2ERalpha. When AhR and ERalpha both were highly expressed, TCDD and E2 upregulated expression of dual responsive genes CYP1A1 and CYP1B1 in a cumulative manner, increasing the danger of metabolic activation of carcinogens. Whereas TCDDAhR and E2ERalpha appeared to regulate CYP1B1 separately through their binding sites, E2ERalpha increased the TCDD responsiveness and mRNA expression of CYP1A1 in a noncanonical way. In conclusion, AhR/ERalpha expression pattern, estrogen level, and promoter context determine the genomic action of dioxin in lung adenocarcinoma cells.
Date:
2013-12
Relation:
American Journal of Respiratory Cell and Molecular Biology. 2013 Dec;49(6):1064-1073.
