title: Inhibition of 11beta-hydroxysteroid dehydrogenase eliminates impaired glucocorticoid suppression and induces apoptosis in corticotroph tumor cells.
abstract: Cushing's disease is characterized by persistent ACTH secretion under hypercortisolemia. In an attempt to clarify the molecular mechanism, we examined the effect of 11beta-hydroxysteroid dehydrogenase (HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11beta-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 11beta-HSD2 because only cortisol, a substrate of 11beta-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11beta-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11beta-HSD2 may be applicable to the medical therapy for Cushing's disease.
authors.affiliation: Departments of Clinical Pathophysiology, Nagoya University Graduate School of Medicine and Hospital, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nigawara
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshida
authors.forename: Machiko
authors.initials: M
authors.lastname: Kambayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sashinami
authors.forename: Kozo
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suda
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000236:Adenoma / Q000150:complications / Q000201:enzymology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002229:Carbenoxolone / Q000494:pharmacology; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005938:Glucocorticoids / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism*; D051379:Mice; D047748:Pituitary ACTH Hypersecretion / Q000201:enzymology* / Q000209:etiology; D010911:Pituitary Neoplasms / Q000150:complications / Q000201:enzymology*
chemical_list: D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006854:Hydrocortisone