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DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells

The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolim...

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Autores principales: Mangili, Federica, Esposito, Emanuela, Treppiedi, Donatella, Catalano, Rosa, Marra, Giusy, Di Muro, Genesio, Barbieri, Anna Maria, Locatelli, Marco, Lania, Andrea G., Mangone, Alessandra, Spada, Anna, Arosio, Maura, Peverelli, Erika, Mantovani, Giovanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204243/
https://www.ncbi.nlm.nih.gov/pubmed/35721701
http://dx.doi.org/10.3389/fendo.2022.867822
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author Mangili, Federica
Esposito, Emanuela
Treppiedi, Donatella
Catalano, Rosa
Marra, Giusy
Di Muro, Genesio
Barbieri, Anna Maria
Locatelli, Marco
Lania, Andrea G.
Mangone, Alessandra
Spada, Anna
Arosio, Maura
Peverelli, Erika
Mantovani, Giovanna
author_facet Mangili, Federica
Esposito, Emanuela
Treppiedi, Donatella
Catalano, Rosa
Marra, Giusy
Di Muro, Genesio
Barbieri, Anna Maria
Locatelli, Marco
Lania, Andrea G.
Mangone, Alessandra
Spada, Anna
Arosio, Maura
Peverelli, Erika
Mantovani, Giovanna
author_sort Mangili, Federica
collection PubMed
description The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the 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 p-AKT. The combined treatment of everolimus and cabergoline induced a 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). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
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spelling pubmed-92042432022-06-18 DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells Mangili, Federica Esposito, Emanuela Treppiedi, Donatella Catalano, Rosa Marra, Giusy Di Muro, Genesio Barbieri, Anna Maria Locatelli, Marco Lania, Andrea G. Mangone, Alessandra Spada, Anna Arosio, Maura Peverelli, Erika Mantovani, Giovanna Front Endocrinol (Lausanne) Endocrinology The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a β-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of β-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the 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 p-AKT. The combined treatment of everolimus and cabergoline induced a 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). To test β-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of β-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in β-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments. Frontiers Media S.A. 2022-06-03 /pmc/articles/PMC9204243/ /pubmed/35721701 http://dx.doi.org/10.3389/fendo.2022.867822 Text en Copyright © 2022 Mangili, Esposito, Treppiedi, Catalano, Marra, Di Muro, Barbieri, Locatelli, Lania, Mangone, Spada, Arosio, Peverelli and Mantovani https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Mangili, Federica
Esposito, Emanuela
Treppiedi, Donatella
Catalano, Rosa
Marra, Giusy
Di Muro, Genesio
Barbieri, Anna Maria
Locatelli, Marco
Lania, Andrea G.
Mangone, Alessandra
Spada, Anna
Arosio, Maura
Peverelli, Erika
Mantovani, Giovanna
DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title_full DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title_fullStr DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title_full_unstemmed DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title_short DRD2 Agonist Cabergoline Abolished the Escape Mechanism Induced by mTOR Inhibitor Everolimus in Tumoral Pituitary Cells
title_sort drd2 agonist cabergoline abolished the escape mechanism induced by mtor inhibitor everolimus in tumoral pituitary cells
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204243/
https://www.ncbi.nlm.nih.gov/pubmed/35721701
http://dx.doi.org/10.3389/fendo.2022.867822
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