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This version published online on October 27, 2005
Endocrinology, doi:10.1210/en.2005-0544
A more recent version of this article appeared on February 1, 2006
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Submitted on May 5, 2005
Accepted on October 17, 2005

Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Eliminates Impaired Glucocorticoid Suppression and Induces Apoptosis in Corticotroph Tumor Cells

Takeshi Nigawara, Yasumasa Iwasaki*, Masato Asai, Masanori Yoshida, Machiko Kambayashi, Hiroshi Sashinami, Kozo Hashimoto, and Toshihiro Suda

Departments of Clinical Pathophysiology (T.N., Y.I., M.K.) and Medicine (M.A., M.Y.), Nagoya University Graduate School of Medicine and Hospital, Nagoya 466-8550; Department of Endocrinology, Metabolism and Infectious Diseases (T.N., T.S.) and Bacteriology (H.S.), Hirosaki University School of Medicine, Hirosaki 036-8562; Department of Endocrinology, Metabolism, and Nephrology (Y.I., K.H.), Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku 783-8505; Japan

* To whom correspondence should be addressed. E-mail: iwasaki{at}med.kochi-u.ac.jp.

Cushing's disease is characterized by persistent ACTH secretion under hypercortisolemia. In an attempt to clarify the molecular mechanism, we examined the effect of 11{beta}-hydroxysteroid dehydrogenase (11{beta}-HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11{beta}-HSD2, as well as -HSD1, was expressed in the cells, and that its inhibition by carbenoxolone (CBX) significantly improved the negative feedback effect of glucocorticoid. CBX also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11{beta}-HSD2, because only cortisol, a substrate of 11{beta}-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11{beta}-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11{beta}-HSD2 may be applicable to the medical therapy for Cushing's disease.
Key words: Cushing's disease • 11{beta}-hydroxysteroid dehydrogenase • glucocorticoid • pituitary tumor • apoptosis






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