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

• Published in: Cancers 2023-06, Vol.15 (12), p.3218
• Main Authors: Di Muro, Genesio, Mangili, Federica, Esposito, Emanuela, Barbieri, Anna Maria, Catalano, Rosa, Treppiedi, Donatella, Marra, Giusy, Nozza, Emma, Lania, Andrea G A, Ferrante, Emanuele, Locatelli, Marco, Arosio, Maura, Peverelli, Erika, Mantovani, Giovanna
• Format: Article
• Language: English
• Subjects: Agonists; Antibiotics; Arrestin; Biological products industry; Brain tumors; Cabergoline; Cell culture; Cell growth; Cell proliferation; Comparative analysis; Dopamine; Dopamine D2 receptors; Dopamine receptors; G proteins; Kinases; Ligands; Neuroendocrine tumors; Pertussis; Pertussis toxin; Phenols; Pituitary; Pituitary hormones; Proteins; Signal transduction; Software; Tumor cell lines; Tumor cells; Tumors; Whooping cough
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15123218

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%, < 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 ( = 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.