β-arrestin expression in corticotroph tumor cells is modulated by glucocorticoids

Federico Gatto, Richard A. Feelders, Rob van der Pas, Peter van Koetsveld, Eleonora Bruzzone, Marica Arvigo, Fadime Dogan, Steven Lamberts, Diego Ferone, Leo Hofland

Research output: Contribution to journalArticlepeer-review

Abstract

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 β-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 β-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and β-arrestin expression was evaluated at mRNA and protein levels. Futhermore, β-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 β-arrestin 1 mRNA expression and a decrease in β-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of β-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored β-arrestin expression to basal levels after 72 h. The evaluation of β-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between β-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on β-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 β-arrestin isofoms in corticotroph tumor cells. Since β-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.

Original languageEnglish
Pages (from-to)101-113
Number of pages13
JournalThe Journal of endocrinology
Volume245
Issue number1
DOIs
Publication statusPublished - Apr 1 2020

Keywords

  • AtT20 cells
  • corticotroph adenoma
  • Cushing’s disease
  • glucocorticoids
  • β-arrestins

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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