Abstract
Some epidemiological studies suggest women may be at greater risk for lung cancer than men. Hydroxyestradiols (OHE 2 ) are genotoxic and considered as carcinogenic metabolites of estrogens. In this study, we demonstrate that treatment with 0.1 or 1nM 2/4OHE 2 significantly increased intracellular oxidative stress, nuclear factor kappa B (NF-κB) activity, and cyclooxygenase-2 (COX-2) expression within 24 h in human bronchial epithelial cells BEAS-2B. Cotreatment with the NF-κB inhibitor, Bay 117085, prevented OHE 2 -induced COX-2 mRNA accumulation, suggesting that OHE 2 induced COX-2 expression via the NF-κB dependent pathway. Furthermore, cotreatment with 10nM 17-beta estradiol (E 2 ) significantly enhanced OHE 2 -increased intracellular oxidative stress and significantly increased not only NF-κB 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 OHE 2 and 10nM E 2 . To understand the enhancement mechanism between OHE 2 and E 2 , 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 E 2 and OHE 2 in BEAS-2B cells. Similarly, Bay 117085 prevented PGE2 secretion induced by the cotreatment of E 2 and OHE 2 in rat lung slice cultures. These results suggest that E 2 enhanced OHE 2 -increased intracellular oxidative stress which increased NF-κB 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. © The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.