Inhibition of 11beta-hydroxysteroid dehydrogenase eliminates impaired glucocorticoid suppression and induces apoptosis in corticotroph tumor cells.
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.
Nigawara
Takeshi
T
Departments of Clinical Pathophysiology, Nagoya University Graduate School of Medicine and Hospital, Japan.
Iwasaki
Yasumasa
Y
Asai
Masato
M
Yoshida
Masanori
M
Kambayashi
Machiko
M
Sashinami
Hiroshi
H
Hashimoto
Kozo
K
Suda
Toshihiro
T
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*
D005938:Glucocorticoids; D000324:Adrenocorticotropic Hormone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006854:Hydrocortisone