Prereceptor regulation of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation.
Isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) act at a prereceptor level to regulate the tissue-specific availability of active glucocorticoids. To examine the effect of this on cell proliferation and differentiation, we have developed transfectant variants of a rat osteosarcoma cell line that express cDNA for 11beta-HSD1 (ROS 17/2.8beta1) or 11beta-HSD2 (ROS 17/2.8beta2). ROS 17/2.8beta1 showed net conversion of cortisone to cortisol whereas ROS 17/2.8beta2 showed only inactivation of cortisol to cortisone. There was no significant difference in glucocorticoid receptor (GR) expression between the different clones. However, in proliferation and differentiation studies, ROS 17/2.8beta2 cells were completely resistant to cortisol. In contrast, ROS 17/2.8beta1 were sensitive to both cortisone and cortisol. Expression of 11beta-HSD1 decreased cell proliferation whereas 11beta-HSD2 increased proliferation. These responses appear to be due to metabolism of endogenous serum glucocorticoids; proliferation of ROS 17/2.8beta1 decreased further with exogenous cortisone or cortisol whereas ROS 17/2.8beta2 were resistant to both compounds. The pro-proliferative effects of 11beta-HSD2 were abrogated by 18beta-glycyrrhetinic acid, an 11beta-HSD inhibitor, and in cells transfected with cDNA encoding inactive 11beta-HSD2. Data indicate that differential regulation of 11beta-HSD1 and 2 (rather than GR expression) is a key determinant of cell proliferation. Dysregulated expression of 11beta-HSD2 may be a novel feature of tumorigenesis.
Rabbitt
Elizabeth H
EH
Division of Medical Sciences, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK.
Lavery
Gareth G
GG
Walker
Elizabeth A
EA
Cooper
Mark S
MS
Stewart
Paul M
PM
Hewison
Martin
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003348:Cortisone / Q000037:antagonists & inhibitors / Q000378:metabolism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468386:HSD11B1 protein, human; C468387:HSD11B2 protein, human; D003348:Cortisone; D006854:Hydrocortisone