11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy.
The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11beta-HSD1 and 2) have well-defined roles in the tissue-specific metabolism of glucocorticoids which underpin key endocrine mechanisms such as adipocyte differentiation (11beta-HSD1) and mineralocorticoid action (11beta-HSD2). However, in recent studies we have shown that the effects of 11beta-HSD1 and 2 are not restricted to distinct tissue-specific hormonal functions. Studies of normal fetal and adult tissues, as well as their tumor equivalents, have shown a further dichotomy in 11beta-HSD expression and activity. Specifically, most normal glucocorticoid receptor (GR)-rich tissues such as adipose tissue, bone, and pituitary cells express 11beta-HSD1, whereas their fetal equivalents and tumors express 11beta-HSD2. We have therefore postulated that the ability of 11beta-HSD1 to generate cortisol acts as an autocrine anti-proliferative, pro-differentiation stimulus in normal adult tissues. In contrast, the cortisol-inactivating properties of 11beta-HSD2 lead to pro-proliferative effects, particularly in tumors. This proposal is supported by experiments in vitro which have demonstrated divergent effects of 11beta-HSD1 and 2 on cell proliferation. Current studies are aimed at (1) characterizing the underlying mechanisms for a "switch" in 11beta-HSD isozyme expression in tumors; (2) defining the molecular targets for glucocorticoids as regulators of cell proliferation; (3) evaluating the potential for targeting glucocorticoid metabolism as therapy for some cancers. These and other issues are discussed in the present review.
Rabbitt
E H
EH
Department of Endocrinology, Division of Medical Sciences, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK.
Gittoes
N J L
NJ
Stewart
P M
PM
Hewison
M
M
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology*
D007527:Isoenzymes; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases