Expression of 11 beta-hydroxysteroid dehydrogenase type 2 in an ACTH-producing small cell lung cancer

Non-pituitary tumors that produce adrenocorticotropic hormone (ACTH) exhibi t resistance to the normal feedback effects of glucocorticoids on proopiome lanocortin (POMC) gene expression. This glucocorticoid resistance is typica lly complete, although some tumors show only relative glucocorticoid resist ance in the clinical setting. The molecular mechanisms responsible for thes e clinical pathophysiologic observations are unknown, but might include glu cocorticoid receptor defects or aberrant expression of enzymes or transport ers that exclude glucocorticoids from access to their intracellular recepto rs. We examined whether ACTH-producing non-pituitary tumor cells might expr ess 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), the principal 'gate keeper' enzyme known to metabolize glucocorticoids. 11 beta-HSD mRNA and en zyme activity were assessed in DMS-79 cells, a Line derived from an ACTH-pr oducing small cell lung cancer. RT-PCR studies showed expression of mRNA en coding 11 beta-HSD2 but not 11 beta-HSD in DMS-79 cells. Control human fibr oblasts expressed predominantly 11 beta-HSD1 but also had detectable 11 bet a-HSD2 mRNA, while HepG2 hepatoma cells also expressed only 11 beta-HSD2, m RNA. Whole cell assays in DMS-79 cells revealed 11 beta-HSD activity with a K-m for cortisol of 26.1 +/- 9.0 nM and V-max of 57.0 +/- 5.9 pmol/h/mg pr otein. HepG2 cells expressed a similar high affinity enzyme activity, while control fibroblasts expressed 11 beta-HSD activity with a K-m for cortisol of 652 nM. Conversion of cortisol to cortisone in DMS-79 cells was inhibit ed to 7% of baseline by addition of 10 mu M glycyrrhetinic acid. Dexamethas one (20 nM) was converted to a single product in DMS-79 cells at a rate of 17.2 pmol/h/mg protein; this activity was also inhibited by glycyrrhetinic acid. We conclude that DMS-79 cells express 11 beta-HSD2. While DMS-79 cell s harbor additional defects in glucocorticoid signaling, these data suggest that expression of 11 beta-HSD2 might contribute to the development of the glucocorticoid-resistant phenotype of some ACTH-producing tumors, (C) 1998 Published by Elsevier Science Ltd. All rights reserved.