期刊
JOURNAL OF ENDOCRINOLOGY
卷 245, 期 1, 页码 101-113出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-19-0311
关键词
beta-arrestins; Cushing's disease; corticotroph adenoma; glucocorticoids; AtT20 cells
Pituitary-directed medical treatment for Cushing's disease (CD) is currently represented by membrane receptor targeting drugs (somatostatin analogs and dopamine agonists). Somatostatin and dopamine receptors are regulated by beta-arrestins, which have been shown to be differentially regulated by glucocorticoids in non-neuroendocrine cells. In this study we investigated the effects of glucocorticoids on beta-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and beta-arrestin expression was evaluated at mRNA and protein levels. Futhermore, beta-arrestin mRNA expression was evaluated in 17 human corticotroph adenoma samples and correlated to patients' pre-operative cortisol levels. We observed that Dex treatment induced a time-dependent increase in beta-arrestin 1 mRNA expression and a decrease in beta-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of beta-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored beta-arrestin expression to basal levels after 72 h. The evaluation of beta-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between beta-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on beta-arrestin levels was confirmed by the analysis of two samples from a single patient, which underwent adenomectomy twice, with different pre-operative cortisol levels. In conclusion, glucocorticoids induce an inverse modulation of the two beta-arrestin isofoms in corticotroph tumor cells. Since beta-arrestins regulate membrane receptor functions, this finding may help to better understand the variable response to pituitary-targeting drugs in patients with Cushing's disease.
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