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

Author:

Di Muro Genesio12,Mangili Federica3ORCID,Esposito Emanuela14,Barbieri Anna Maria1ORCID,Catalano Rosa1,Treppiedi Donatella3,Marra Giusy1,Nozza Emma14,Lania Andrea G. A.56,Ferrante Emanuele3ORCID,Locatelli Marco78,Arosio Maura13ORCID,Peverelli Erika13ORCID,Mantovani Giovanna13ORCID

Affiliation:

1. Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy

2. Department of Experimental Medicine, University Sapienza of Rome, 00100 Rome, Italy

3. Endocrinology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

4. PhD Program in Experimental Medicine, University of Milan, 20100 Milan, Italy

5. Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy

6. Endocrinology and Diabetology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, 20089 Rozzano, Italy

7. Neurosurgery Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy

8. Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy

Abstract

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%, p < 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 (n = 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.

Funder

Associazione Italiana Ricerca Cancro

Progetti di Ricerca di Interesse Nazionale

Italian Ministry of Health

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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