Endocrine Abstracts (2002) 3 P146

Inhibition of 11beta-HSD2 has an anti-proliferative effect on pituitary tumour cells

EH Rabbitt, IJ Bujalska, PM Stewart, MC Sheppard, M Hewison & NJL Gittoes

Department of Medicine, University of Birmingham, Birmingham, UK.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by an inhibition of cell proliferation. More contentious is their anti-proliferative action and possible tumour modifying effects in neoplastic tissues. Central to the action of GCs in target tissues is the expression and function of two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) that serve to interconvert active cortisol (F) and inactive cortisone (E). 11beta-HSD type 1 (11beta-HSD1) predominantly converts E to F; the type 2 enzyme (11beta-HSD2) serves to inactivate F to E. Our previous studies of 11beta-HSD expression in pituitary adenomas have demonstrated a dramatic switch in isozyme expression from 11beta-HSD1 in normal pituitaries to 11beta-HSD2 in pituitary adenomas. We have assessed the functional consequences of this observed change in isozyme expression in primary human pituitary cultures (n=6). Cultured cells were assayed after 3 days for 11beta-HSD activity and cell proliferation was assessed by 3H-thymidine incorporation in the basal state and following treatment with glycyrrhetinic acid (GE), an inhibitor of 11beta-HSD. All primary pituitary cultures showed significant 11beta-HSD2 activity (F to E conversion, 71.9 pmol/hr/mg protein +/- 22.3) but none exhibited measurable activity for 11beta-HSD1. Proliferation measured by 3H-thymidine incorporation (n=3) showed that in the basal state, pituitary-derived cells were proliferating in culture. Addition of GE to the culture medium resulted in a 65.5% (+/-15) reduction in cell proliferation. We propose that the combination of significant 11beta-HSD2 activity and undetectable 11beta-HSD1 activity in pituitary adenomas will metabolise active F to inactive E, thereby removing the anti-proliferative effect of F. Addition of GE inhibits 11beta-HSD2, restoring local concentrations of F, which imposes an anti-proliferative influence. Our current data continue to support a central role for 11beta-HSDs and GC metabolism in neoplastic growth.

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