A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells
The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2′s antimitotic effec...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/12/3218 |
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| author | Genesio Di Muro Federica Mangili Emanuela Esposito Anna Maria Barbieri Rosa Catalano Donatella Treppiedi Giusy Marra Emma Nozza Andrea G. A. Lania Emanuele Ferrante Marco Locatelli Maura Arosio Erika Peverelli Giovanna Mantovani |
| author_facet | Genesio Di Muro Federica Mangili Emanuela Esposito Anna Maria Barbieri Rosa Catalano Donatella Treppiedi Giusy Marra Emma Nozza Andrea G. A. Lania Emanuele Ferrante Marco Locatelli Maura Arosio Erika Peverelli Giovanna Mantovani |
| author_sort | Genesio Di Muro |
| collection | DOAJ |
| description | The molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2′s antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (−40.2 ± 20.4% vs. −21 ± 10.9%, <i>p</i> < 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline’s antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures (<i>n</i> = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors. |
| first_indexed | 2024-03-09T10:57:21Z |
| format | Article |
| id | doaj.art-845c463e99fa401a8223098880f6c3cd |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T10:57:21Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-845c463e99fa401a8223098880f6c3cd2023-12-01T01:33:07ZengMDPI AGCancers2072-66942023-06-011512321810.3390/cancers15123218A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor CellsGenesio Di Muro0Federica Mangili1Emanuela Esposito2Anna Maria Barbieri3Rosa Catalano4Donatella Treppiedi5Giusy Marra6Emma Nozza7Andrea G. A. Lania8Emanuele Ferrante9Marco Locatelli10Maura Arosio11Erika Peverelli12Giovanna Mantovani13Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyEndocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyEndocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, ItalyEndocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, ItalyNeurosurgery Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyDepartment of Clinical Sciences and Community Health, University of Milan, 20122 Milan, ItalyThe molecular events underlying the variable effectiveness of dopamine receptor type 2 (DRD2) agonists in pituitary neuroendocrine tumors (PitNETs) are not known. Besides the canonical pathway induced by DRD2 coupling with Gi proteins, the β-arrestin 2 pathway contributes to DRD2′s antimitotic effects in PRL- and NF-PitNETs. A promising pharmacological strategy is the use of DRD2-biased agonists that selectively activate only one of these two pathways. The aim of the present study was to compare the effects of two biased DRD2 ligands, selectively activating the G protein (MLS1547) or β-arrestin 2 (UNC9994) pathway, with unbiased DRD2 agonist cabergoline in PRL- and NF-PitNET cells. In rat tumoral pituitary PRL-secreting MMQ cells, UNC9994 reduced cell proliferation with a greater efficacy compared to cabergoline (−40.2 ± 20.4% vs. −21 ± 10.9%, <i>p</i> < 0.05), whereas the G-protein-biased agonist induced only a slight reduction. β-arrestin 2 silencing, but not pertussis toxin treatment, reverted UNC9994 and cabergoline’s antiproliferative effects. In a cabergoline-resistant PRL-PitNET primary culture, UNC9994 inhibited cell proliferation and PRL release. In contrast, in NF-PitNET primary cultures (<i>n</i> = 23), biased agonists did not show better antiproliferative effects than cabergoline. In conclusion, the preferential activation of the β-arrestin 2 pathway by UNC9994 improves DRD2-mediated antiproliferative effects in PRL-PitNETs, suggesting a new pharmacological approach for resistant or poorly responsive tumors.https://www.mdpi.com/2072-6694/15/12/3218dopamine receptor type 2pituitary tumorsbeta arrestin 2 |
| spellingShingle | Genesio Di Muro Federica Mangili Emanuela Esposito Anna Maria Barbieri Rosa Catalano Donatella Treppiedi Giusy Marra Emma Nozza Andrea G. A. Lania Emanuele Ferrante Marco Locatelli Maura Arosio Erika Peverelli Giovanna Mantovani A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells Cancers dopamine receptor type 2 pituitary tumors beta arrestin 2 |
| title | A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells |
| title_full | A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells |
| title_fullStr | A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells |
| title_full_unstemmed | A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells |
| title_short | A β-Arrestin 2-Biased Dopamine Receptor Type 2 (DRD2) Agonist Is More Efficacious Than Cabergoline in Reducing Cell Proliferation in PRL-Secreting but Not in Non-Functioning Pituitary Tumor Cells |
| title_sort | β arrestin 2 biased dopamine receptor type 2 drd2 agonist is more efficacious than cabergoline in reducing cell proliferation in prl secreting but not in non functioning pituitary tumor cells |
| topic | dopamine receptor type 2 pituitary tumors beta arrestin 2 |
| url | https://www.mdpi.com/2072-6694/15/12/3218 |
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