Abnormal expression of 11beta-hydroxysteroid dehydrogenase 2 in primary cultures of human pituitary adenomas
EH Rabbitt, IJ Bujalska, PM Stewart, M Hewison & NJL Gittoes
Glucocorticoids (GCs) mediate many of their physiological effects through inhibition of cell proliferation. More contentious is the antiproliferative action of GCs and their possible tumour-modifying effects in neoplastic tissues. However, in recent studies we have shown that 'prereceptor' metabolism of GCs by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is a pivotal determinant of cell proliferation and tumour formation. Two isozymes of 11beta-HSD interconvert active cortisol and inactive cortisone within corticosteroid target tissues. In normal pituitary tissue the predominant isozyme is 11beta-HSD1 (cortisol synthesis), whereas in pituitary tumours there is a dramatic switch to 11beta-HSD2 (cortisol inactivation). Further studies in vitro have shown that inappropriate expression of 11beta-HSD2 is associated with increased cell proliferation, whilst 11beta-HSD1 provides an antiproliferative signal. In data presented here we have assessed the functional consequence of this observed change in 11beta-HSD isozyme expression using primary cultures of 10 human non-functioning pituitary tumour cells. Tumour cells cultured for three days were assayed for 11beta-HSD expression (RT-PCR) and activity (quantitative TLC analysis), and rates of cell proliferation were determined by 3H-thymidine incorporation. All primary cultures showed significant levels of 11beta-HSD2 activity (cortisol to cortisone conversion, 71.9 plus/minus 22.3 (SD) pmoles/hr/mg protein). No 11beta-HSD1 expression or activity was detectable in any of the tumour cultures. 3H-thymidine studies showed that inhibition of 11beta-HSD2 following treatment with glycyrrhetinic acid (1mM, 24 hours) resulted in a decrease in tumour cell proliferation (34.5 plus/minus 15% inhibition compared to untreated controls). Importantly, glycyrrhetinic acid also potentiated the antiproliferative effects of exogenously administered cortisol providing evidence that its actions are mediated, at least in part, by attenuation of local glucocorticoid action by 11beta-HSD2. We propose that a switch in 11beta-HSD isozyme expression in the pituitary may confer a growth advantage and thus contribute to pituitary tumourigenesis. The possibility of modulating 11beta-HSD2 activity in pituitary tumours may offer potentially novel therapies.