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11beta-hydroxysteroid dehydrogenases, cell proliferation and malignancy
E H Rabbitt1, N J L Gittoes, P M Stewart
1Department of Endocrinology, Division of Medical Sciences, Institute of Clinical Research, Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, UK.
The Journal of Steroid Biochemistry and Molecular Biology
|August 29, 2003
Summary
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) promotes cell differentiation, while 11beta-HSD2 promotes proliferation, especially in tumors. This enzyme switch impacts cancer therapy.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and type 2 (11beta-HSD2) metabolize glucocorticoids.
- These enzymes have distinct roles in tissue-specific functions like adipocyte differentiation and mineralocorticoid action.
- Recent studies reveal non-canonical functions and a dichotomy in 11beta-HSD expression between normal tissues and tumors.
Purpose of the Study:
- To investigate the opposing roles of 11beta-HSD1 and 11beta-HSD2 in cell proliferation and differentiation.
- To explore the switch in 11beta-HSD isozyme expression in tumors.
- To define glucocorticoid molecular targets regulating cell proliferation and evaluate targeting glucocorticoid metabolism for cancer therapy.
Main Methods:
- Comparative analysis of 11beta-HSD expression in normal fetal/adult tissues and tumor equivalents.
- In vitro experiments demonstrating the effects of 11beta-HSD1 and 11beta-HSD2 on cell proliferation.
- Mechanistic studies on the switch in 11beta-HSD isozyme expression in cancer.
Main Results:
- Normal glucocorticoid receptor (GR)-rich tissues (e.g., adipose, bone) express 11beta-HSD1, promoting anti-proliferative and pro-differentiation effects.
- Fetal tissues and tumors express 11beta-HSD2, which inactivates cortisol, leading to pro-proliferative effects.
- In vitro studies confirm divergent impacts of 11beta-HSD1 and 11beta-HSD2 on cell proliferation.
Conclusions:
- 11beta-HSD1 acts as an autocrine anti-proliferative, pro-differentiation factor in normal adult tissues.
- 11beta-HSD2's cortisol-inactivating function promotes proliferation, particularly in tumor cells.
- Targeting glucocorticoid metabolism offers potential therapeutic strategies for certain cancers.