β-arrestin expression in corticotroph tumor cells is modulated by glucocorticoids
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:245 |
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| Enthalten in: |
The Journal of endocrinology - 245(2020), 1 vom: 18. Apr., Seite 101-113 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gatto, Federico [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.10.2020 Date Revised 19.10.2020 published: Print Citation Status MEDLINE |
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| doi: |
10.1530/JOE-19-0311 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM30622271X |
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| 500 | |a Date Revised 19.10.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AtT20 cells | |
| 650 | 4 | |a Cushing’s disease | |
| 650 | 4 | |a corticotroph adenoma | |
| 650 | 4 | |a glucocorticoids | |
| 650 | 4 | |a β-arrestins | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a beta-Arrestin 1 |2 NLM | |
| 650 | 7 | |a beta-Arrestin 2 |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 650 | 7 | |a Cabergoline |2 NLM | |
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| 700 | 1 | |a Feelders, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a van der Pas, Rob |e verfasserin |4 aut | |
| 700 | 1 | |a van Koetsveld, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Bruzzone, Eleonora |e verfasserin |4 aut | |
| 700 | 1 | |a Arvigo, Marica |e verfasserin |4 aut | |
| 700 | 1 | |a Dogan, Fadime |e verfasserin |4 aut | |
| 700 | 1 | |a Lamberts, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Ferone, Diego |e verfasserin |4 aut | |
| 700 | 1 | |a Hofland, Leo |e verfasserin |4 aut | |
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