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Abnormal expression of 11β-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation

Oncogene volume 22, pages 1663–1667 (2003)Cite this article

Abstract

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11β-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11β-HSD2 was readily demonstrable. Here we have used real-time RT–PCR to quantify expression of mRNA for 11 β-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11β-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11β-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11β-HSD2 activity (71.9±22.3 pmol/h/mg protein (mean±s.d.)) but no detectable 11β-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11β-HSD2 inhibitor) resulted in a 30.3±7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11β-HSDl to 11β-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11β-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.

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Acknowledgements

We thank Mr Alan Johnson, Mrs Ros Mitchell and Mr Richard Walsh for providing us with pituitary adenoma tissue. In addition, Dr Damian Morris and Dr Iwona Bujalska provided invaluable help in establishing primary pituitary cultures. This research is supported by the MRC, Wellcome Trust (UK) and the Former United Hospitals Birmingham Endowment Fund. PMS is an MRC Senior Clinical Fellow and NJLG holds and MRC Career Establishment Grant.

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  1. Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, B152TH, UK

    E H Rabbitt, J Ayuk, K Boelaert, M C Sheppard, M Hewison, P M Stewart & N J L Gittoes

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  1. E H Rabbitt
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  2. J Ayuk
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Correspondence to P M Stewart.

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Rabbitt, E., Ayuk, J., Boelaert, K. et al. Abnormal expression of 11β-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation. Oncogene 22, 1663–1667 (2003). https://doi.org/10.1038/sj.onc.1206293

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