Glucocorticoids (GCs) induce surfactant synthesis in the late fetal lung. Deficient GC action causes respiratory distress syndrome. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inert cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone), thus amplifying intracellular GC action. We investigated 11beta-HSD1 in the late fetal lung using the licorice-derived inhibitor, glycyrrhetinic acid (GE), in pregnant rats (day 13 of gestation until term). Control fetal mice and rats showed high 11beta-HSD activity in the late fetal lung; levels of plasma 11-dehydrocorticosterone were also high. Reduction/loss of pulmonary 11beta-HSD1 activity in GE-treated rats substantially impaired fetal lung maturation. Lungs from GE-exposed rats had lower surfactant protein-A (mRNA and protein) levels and reduced amniotic fluid lecithin/sphingomyelin ratios. There was a marked depletion of lung surfactant before and after birth, as detected by both light and electron microscopy. The data emphasize the importance of 11beta-HSD1 in amplifying key GC-dependent maturational processes in the late fetal lung.
To verify the relevance of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in controlling breast-cancer cell growth, we have evaluated the correlation of 11beta-HSD2 expression and antiproliferative effects of glucocorticosteroids (GCs) on breast cancer cell proliferation. We cloned human 11beta-HSD2 cDNA into the expression vector pBK-CMV. The interspersing lac promoter region was deleted, achieving differential translational efficiency. The constructs were stably transfected into wild-type MCF-7 breast-cancer cells possessing almost no oxidative and no reductive 11beta-HSD activity. Low (times 7) and high (times 718) 11beta-HSD2 overexpression was achieved. We compared growth behavior of transfected cells In the presence of GCs to MCF-7 cells transfected with pBK-CMV alone (internal control). The antiproliferative effects of GCs were reversed and total cell growth boosted by overexpression of 11beta-HSD2; about 50 % of the increase in cell proliferation was attained by low 11beta-HSD2 overexpression, while high enzyme overexpression led to an increase in cell growth of about 120 %. Using direct evidence, this study shows 11beta-HSD2 to impair antiproliferative glucocorticosteroid effects, thus acting as an enzymatic shield aggravating breast-cancer cell growth. These results indicate a possible therapeutic role for 11beta-HSD inhibitors in the treatment of breast cancer.
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