Carcinogenesis Advance Access originally published online on February 1, 2007
Carcinogenesis 2007 28(7):1606-1612; doi:10.1093/carcin/bgm013
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Increase of carcinogenic risk via enhancement of cyclooxygenase-2 expression and hydroxyestradiol accumulation in human lung cells as a result of interaction between BaP and 17-beta estradiol
1 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, Republic of China
2 Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
3 Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan
* To whom correspondence should be addressed. Tel: +886 37 246 166 ext. 36508; Fax: +886 37 587 406; Email: pplin{at}nhri.org.tw
Animal studies demonstrated that females are more susceptible than males to benzo[a]pyrene (BaP)-induced toxicities, including lung carcinogenesis. Elevation of cyclooxygenase-2 (COX-2) expression has been shown to increase the risk of cancer development. BaP induces COX-2 expression, and an interaction between BaP and estrogen in relation to COX-2 expression is suspected. In the present study, 10 µM BaP alone only slightly increased COX-2 mRNA expression and 10 nM 17-beta estradiol (E2) alone slightly increased prostaglandin E2 (PGE2) secretion in human bronchial epithelial cells. However, co-treatment with BaP and E2 potentiated COX-2 mRNA expression and significantly elevated PGE2 secretion. Utilizing specific inhibitors and reporter assays, we further investigated the potentiation mechanisms of E2 on BaP-induced COX-2 expression. First, E2 activated estrogen receptor to increase PGE2 secretion, which directly increased COX-2 expression. Second, E2 potentiated BaP-induced nuclear factor-
B (NF-B) activation, which regulates COX-2 expression. Third, although the aryl hydrocarbon receptor (AhR) did not play a role in BaP-induced COX-2 expression, the potentiation effect of E2 itself was AhR dependent. We further demonstrated that BaP induced the production of genotoxic E2 metabolites (2- and 4-hydroxyestradiols) via AhR-up-regulated cytochromes P450 1A1 and 1B1. These metabolites could directly activate NF-B to further promote COX-2 mRNA expression in human lung epithelial cells. These findings were further supported by increased PGE2 secretion in rat lung slice cultures. Our findings that the BaP–E2 interaction enhanced COX-2 expression and hydroxyestradiol accumulation in the media of cultivated lung cells and tissues provide the needed scientific basis for higher risk of BaP-associated lung cancer in females.
Abbreviations: AhR, aryl hydrocarbon receptor; BaP, benzo[a]pyrene; COX-2, cyclooxygenase-2; CYP1A1, cytochrome P450 1A1; CYP1B1, cytochrome P450 1B1; DMF, 3',4'-dimethoxyflavone; DMSO, dimethyl sulfoxide; E2, 17-beta estradiol; ER, estrogen receptor; LHC, laboratory of human carcinogenesis MeOE2, methoxyestradiol; NF-B, nuclear factor-B; OHE2, hydroxyestradiol; PGE2, prostaglandin E2; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin
Received September 4, 2006; revised December 18, 2006; accepted January 17, 2007.
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  C.-C. Ho, Y.-C. Ling, L. W. Chang, H.-T. Tsai, M.-H. Tsai, and P. Lin 17-Beta Estradiol and Hydroxyestradiols Interact via the NF-Kappa B Pathway to Elevate Cyclooxygenase 2 Expression and Prostaglandin E2 Secretion in Human Bronchial Epithelial Cells Toxicol. Sci., August 1, 2008; 104(2): 294 - 302. [Abstract] [Full Text] [PDF]
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