title: Dioxin and estrogen signaling in lung adenocarcinoma cells with different aryl hydrocarbon receptor/estrogen receptor α phenotypes.
abstract: Evidence suggests that estrogen affects the pulmonary response to carcinogenic pollutants, such as dioxins. In this study, we examined dioxin and estrogen signaling cross-talk in lung adenocarcinoma cell lines that were engineered to exhibit different aryl hydrocarbon receptor (AhR)/estrogen receptor (ER) α phenotypes. Data showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) weakly antagonized estrogen-activated ERα activity in cells expressing abundant ERα, but little AhR. Increase of AhR expression or presence of a dioxin-responsive element in proximity silenced the antiestrogenic effect of TCDD. AhR was bound to dioxin-responsive element and transcriptionally active in both TCDD-untreated and -treated lung adenocarcinoma cells. 17β-estradiol (E2) reduced basal and TCDD-induced AhR activity only in ERα-positive cells. AhR and ERα exhibited a protein-protein interaction in the presence of E2. Cotreatment with TCDD moderated this protein interaction. Colocalization of ERα and AhR at the estrogen-responsive site under E2 and TCDD/E2 treatments implied that E2 ∣ ERα might hijack AhR away from the dioxin-responsive site. Increasing the relative expression of AhR to ERα counteracted inhibition of AhR activity by E2 ∣ ERα. When AhR and ERα were both highly expressed, TCDD and E2 up-regulated expression of dual-responsive genes cytochrome P450 (CYP) 1A1 and CYP1B1 in a cumulative manner, increasing the danger of metabolic activation of carcinogens. Whereas TCDD ∣ AhR and E2 ∣ ERα appeared to regulate CYP1B1 separately through their binding sites, E2 ∣ ERα increased the TCDD responsiveness and mRNA expression of CYP1A1 in a noncanonical way. In conclusion, AhR/ERα expression pattern, estrogen level, and promoter context determine the genomic action of dioxin in lung adenocarcinoma cells.
authors.affiliation: 1 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan, Republic of China.
authors.forename: Lun-Cheng
authors.initials: LC
authors.lastname: Kuo
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Cheng
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Lin
authors.forename: Lih-Ann
authors.initials: LA
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000393:Air Pollutants / Q000378:metabolism / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000393:Air Pollutants; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018336:Receptors, Aryl Hydrocarbon; D004958:Estradiol; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1