title: TCDD promotes lung tumors via attenuation of apoptosis through activation of the Akt and ERK1/2 signaling pathways.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan; Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Rong-Jane
authors.initials: RJ
authors.lastname: Chen
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Shih-He
authors.initials: SH
authors.lastname: Siao
authors.affiliation: Department of Nuclear Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Chung-Huei
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Chu-Yung
authors.initials: CY
authors.lastname: Chang
authors.affiliation: National Environmental Health Research Center, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: Louis W
authors.initials: LW
authors.lastname: Chang
authors.affiliation: Department of Surgery, School of Medicine, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan; Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan Town, Taiwan; National Environmental Health Research Center, National Health Research Institutes, Zhunan Town, Taiwan.
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Biomedical Informatics, Asia University, Taichung, Taiwan.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation; D003043:Cocarcinogenesis; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009602:Nitrosamines / Q000008:administration & dosage* / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D002274:Carcinogens, Environmental; D004791:Enzyme Inhibitors; D009602:Nitrosamines; D000072317:Polychlorinated Dibenzodioxins; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D019311:Staurosporine