ECE2019 Poster Presentations Pituitary and Neuroendocrinology 1 (72 abstracts)
β-arrestin 2 expression is required for dopamine receptor type 2 (DRD2) inhibitory effects on Akt phosphorylation and cell proliferation in PRL-secreting and non functioning pituitary tumors
Federica Mangili 1 , Elena Giardino 1 , Donatella Treppiedi 1 , Rosa Catalano 1, , Marco Locatelli 3 , Andrea G Lania 4 , Anna Spada 1 , Maura Arosio 1 , Giovanna Mantovani 1 & Erika Peverelli 1
1Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 2PhD Program in Endocrinological Science, Sapienza University of Rome, Rome, Italy; 3Neurosurgery Unit, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 4Endocrine Unit, IRCCS Humanitas Clinical Institute, Humanitas University, Rozzano, Italy.
Dopamine receptor type 2 (DRD2) agonists (DAs) are the first-choice treatment for PRL-secreting pituitary tumors due to their efficacy in reducing tumor size and hormonal secretion. However, DAs are poorly effective in non-functioning pituitary tumors (NFPTs), despite most of them express DRD2. No correlation between DAs clinical responsiveness and DRD2 expression was found, suggesting post-receptor alterations underlying resistance. DRD2 signaling pathways that control cell proliferation are mostly unknown. In particular, no data are available in pituitary tumor cells about DRD2 effects on Akt activation, a survival and proliferative pathway over-activated in pituitary tumors. In other cell models, a β-arrestin 2-mediated Akt inhibition by DRD2 has been shown. The aim of this study was to investigate the effects of DRD2 activation on Akt phosphorylation (p-Akt) and cell proliferation in human primary cultured NFPT cells and in rat tumoral lactotroph cells MMQ, and to test the involvement of β-arrestin 2. Firstly, Akt inhibitor GSK2110183 reduced cell proliferation in both MMQ (−88.2±3.6%, P<0.001 vs bas) and NFPTs (−41.4±10.9%, P<0.01 vs basal). DRD2 specific agonist BIM53097 inhibited p-Akt in MMQ (−24±7%, P<0.001 vs basal) and in a subset (30%, n=23) of NFPTs (−25±7%, P<0.001 vs basal) (subgroup 1), whereas increased p-Akt (+1.9±1.2 fold vs basal) in the remaining tumors (subgroup 2). Western blot analysis revealed a striking correlation between DRD2 ability to inhibit Akt and β-arrestin 2 expression, since it was expressed only in MMQ and NFPTs subgroup 1, but not subgroup 2. The mechanism by which DRD2 dephosphorylates Akt is G protein-independent, as demonstrated by pertussis toxin treatment in MMQ and NFPTs, and β-arrestin 2 mediated, since β-arrestin 2 silencing prevented DRD2 effects on p-Akt in MMQ. Accordingly, β-arrestin 2 transfection in subgroup 2 NFPTs conferred to DRD2 agonist the ability to inhibit both p-Akt (−23±8%, P<0.05 vs bas) and cell proliferation (−32.1±23.8%, P<0.05 vs bas). In conclusion, these data demonstrate that β-arrestin 2 is required for DRD2 inhibitory effects on Akt phosphorylation and cell proliferation in MMQ cells and NFPTs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NFPTs responsiveness to treatment with DAs.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more