ECE2022 Poster Presentations Pituitary and Neuroendocrinology (127 abstracts)
The positive feedback exerted by mtor inhibitor everolimus in pituitary neuroendocrine tumoral cells is reverted by cabergoline co-treatment
Federica Mangili 1 , Emanuela Esposito 1 , Donatella Treppiedi 1 , Rosa Catalano 1 , Giusy Marra 1 , Genesio Di Muro 1 , Anna Maria Barbieri 1 , Marco Locatelli 2 , Andrea Gerardo Lania 3 , Anna Spada 1 , Maura Arosio 4 , Giovanna Mantovani 4 & Erika Peverelli 1
1University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy; 2Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; 3Endocrine Unit, IRCCS Humanitas Clinical Institute, Humanitas University, Rozzano, Rozzano, Italy; 4Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
The mTOR inhibitor everolimus has been shown to display antimitotic effects on diverse neoplasms, including pituitary neuroendocrine tumors (PitNETs); however, its effect is reduced by an escape mechanism that increases AKT phosphorylation (P-AKT) leading to survival pathway activation. Dopamine receptor type 2 (DRD2) reduces p-AKT in some non-functioning PitNETs (NF-PitNETs) and in lactotrophs MMQ cells, through a α-arrestin 2-dependent mechanism. This study aims to analyze the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing proliferation in primary cultured NF-PitNETs and MMQ cells, to analyze AKT phosphorylation and α-arrestin 2 activity. We found that 9 out of 14 NF-PitNETs were resistant to everolimus 1 nM, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, P< 0.001 vs basal), accordingly increased p27 and reduced cyclin D3 expression. In everolimus unresponsive NF-PitNETs group, 3 h everolimus treatment determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, P< 0.01, vs basal), and this effect was significantly reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed, 1 nM everolimus did not affect MMQ cells proliferation and increased p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, P<0.001 vs basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, P<0.001 vs basal) and AKT activity. The combined treatment of everolimus and cabergoline induced a significant reduction of both cell proliferation (-34.8 ± 18%, P<0.001 vs basal and P<0.05 vs cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, P<0.001 vs basal and P<0.05 vs cabergoline alone). Moreover, to test a possible involvement of α-arrestin 2, silencing experiments were performed in MMQ cells. Our data showed that the lack of α-arrestin 2 prevented everolimus and cabergoline co-treatment inhibitory effects on both AKT activation and cells proliferation. These results unveiled that cabergoline overcomes the everolimus escape mechanism in primary NF-PitNETs cultured and MMQ cells inhibiting AKT phosphorylation, paving the way for a potential role of β-arrestin 2 as a biomarker predicting PitNETs responsiveness to combined therapy with dopamine agonists.
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