Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for PRL-secreting pitui-tary tumors but are poorly effective in non-functioning pituitary neuroendocrine tumors (NF-PitNET). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin2-dependent mechanism in mouse striatum. The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement. We found that DRD2 agonist BIM53097 induced a reduction of p- AKT /total-AKT ratio in MMQ (-32.8±17.6%, p<0.001 vs basal) and in a subset (n=15/41,36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase of p-AKT. The ability of BIM53097 to reduce p-AKT correlated to its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097 and nearly all subgroup 2 NF-PitNETs were resistant. β-arrestin 2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs. In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth. In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs responsiveness to treatment with dopamine agonists.
β-arrestin 2 is required for dopamine receptor type 2 inhibitory effects on AKT phosphorylation and cell proliferation in pituitary tumors / F. Mangili, E. Giardino, D. Treppiedi, A.M. Barbieri, R. Catalano, M. Locatelli, A.G. Lania, A. Spada, M. Arosio, G. Mantovani, E. Peverelli. - In: NEUROENDOCRINOLOGY. - ISSN 0028-3835. - (2021). [Epub ahead of print]
Titolo: | β-arrestin 2 is required for dopamine receptor type 2 inhibitory effects on AKT phosphorylation and cell proliferation in pituitary tumors | |
Autori: | MANGILI, FEDERICA (Primo) GIARDINO, ELENA (Secondo) PEVERELLI, ERIKA MARIA (Ultimo) | |
Settore Scientifico Disciplinare: | Settore MED/13 - Endocrinologia | |
Data di pubblicazione: | 2021 | |
Rivista: | ||
Tipologia: | Article (author) | |
Data ahead of print / Data di stampa: | 8-giu-2020 | |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1159/000509219 | |
Appare nelle tipologie: | 01 - Articolo su periodico |
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