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ToxSci Advance Access originally published online on May 13, 2008
Toxicological Sciences 2008 104(2):294-302; doi:10.1093/toxsci/kfn096
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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

Chia-Chi Ho*, Yong-Chien Ling*,{dagger}, Louis W. Chang{ddagger}, Hui-Ti Tsai{ddagger}, Ming-Hsien Tsai{ddagger} and Pinpin Lin{ddagger},1

* Institute of NanoEngineering and Microsystems, National Tsing Hua University {dagger} Department of Chemistry, National Tsing Hua University {ddagger} Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan

1 To whom correspondence should be addressed at Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan. Fax: +886-37-587-406. E-mail: pplin{at}nhri.org.tw.

Received February 1, 2008; accepted May 8, 2008


  Abstract

Some epidemiological studies suggest women may be at greater risk for lung cancer than men. Hydroxyestradiols (OHE2) are genotoxic and considered as carcinogenic metabolites of estrogens. In this study, we demonstrate that treatment with 0.1 or 1nM 2/4OHE2 significantly increased intracellular oxidative stress, nuclear factor kappa B (NF-{kappa}B) activity, and cyclooxygenase-2 (COX-2) expression within 24 h in human bronchial epithelial cells BEAS-2B. Cotreatment with the NF-{kappa}B inhibitor, Bay 117085, prevented OHE2-induced COX-2 mRNA accumulation, suggesting that OHE2 induced COX-2 expression via the NF-{kappa}B dependent pathway. Furthermore, cotreatment with 10nM 17-beta estradiol (E2) significantly enhanced OHE2-increased intracellular oxidative stress and significantly increased not only NF-{kappa}B activity but also COX-2 levels. As COX-2 participates in biosynthesis of prostaglandin E2 (PGE2), PGE2 secretion was enhanced by the cotreatment of 1nM OHE2 and 10nM E2. To understand the enhancement mechanism between OHE2 and E2, cells were cotreated with an antioxidant, N-acetylcysteine (NAC), or NF-kB inhibitor, Bay 117085. Both NAC and Bay 117085 prevented the enhancement in COX-2 expression and PGE2 secretion by the cotreatment of E2 and OHE2 in BEAS-2B cells. Similarly, Bay 117085 prevented PGE2 secretion induced by the cotreatment of E2 and OHE2 in rat lung slice cultures. These results suggest that E2 enhanced OHE2-increased intracellular oxidative stress which increased NF-{kappa}B activity, COX-2 expression, and PGE2 secretion. Elevated COX-2 expression and PGE2 secretion has been shown to increase the risk of cancer development. Our present data suggest a pathway that contributes an epigenetic mechanism to the overall mechanism of carcinogenesis.

Key Words: nongenotoxic; endocrine; estrogens.


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