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.

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 1 nM 2/4 OHE(2) significantly increased intracellular oxidative stress, nuclear factor kappa B (NF-kappaB) activity, and cyclooxygenase-2 (COX-2) expression within 24 h in human bronchial epithelial cells BEAS-2B. Cotreatment with the NF-kappaB inhibitor, Bay 117085, prevented OHE(2)-induced COX-2 mRNA accumulation, suggesting that OHE(2) induced COX-2 expression via the NF-kappaB 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-kappaB activity but also COX-2 levels. As COX-2 participates in biosynthesis of prostaglandin E2 (PGE2), PGE2 secretion was enhanced by the cotreatment of 1 nM 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-kappaB 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.