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

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

Address all correspondence and requests for reprints to: Yasumasa Iwasaki, M.D., Ph.D., Department of Medicine, Kochi University School of Medicine, 185-1 Kohasu, Oko-cho, Nankoku 783-8505. 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 11ß-hydroxysteroid dehydrogenase (HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11ß-HSD2, as well as -HSD1, was expressed in the cells and that its inhibition by carbenoxolone significantly improved the negative feedback effect of glucocorticoid. Carbenoxolone also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11ß-HSD2 because only cortisol, a substrate of 11ß-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11ß-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11ß-HSD2 may be applicable to the medical therapy for Cushing’s disease.