Exploiting D₂ receptor β‐arrestin2‐biased signalling to suppress tumour growth of pituitary adenomas

Abstract

Background and Purpose Dopamine agonists targeting D2 receptor have been used for decades in treating pituitary adenomas. There has been little clear evidence implicating the canonical G protein signalling as the mechanism by which D2 receptor suppresses the growth of pituitary tumours. We hypothesize that β‐arrestin2‐dependent signalling is the molecular mechanism dictating D2 receptor inhibitory effects on pituitary tumour growth. Experimental Approach The involvement of G protein and β‐arrestin2 in bromocriptine‐mediated growth suppression in rat MMQ and GH3 tumour cells was assessed. The anti‐growth effect of a β‐arrestin2‐biased agonist, UNC9994, was tested in cultured cells, tumour‐bearing nude mice and primary cultured human pituitary adenomas. The effect of G protein signalling on tumour growth was also analysed by using a G protein‐biased agonist, MLS1547, and a Gβγ inhibitor, gallein, in vitro. Key Results β‐arrestin2 signalling but not G protein pathways mediated the suppressive effect of bromocriptine on pituitary tumour growth. UNC9994 inhibited pituitary tumour cell growth in vitro and in vivo. The suppressive function of UNC9994 was obtained by inducing intracellular reactive oxygen species generation through downregulating mitochondrial complex I subunit NDUFA1. The effects of Gαi/o signalling and Gβγ signalling via D2 receptor on pituitary tumour growth were cell‐type‐dependent. Conclusion and Implications Given the very low expression of Gαi/o proteins in pituitary tumours and the complexity of the responses of pituitary tumours to G protein signalling pathways, our study reveals D2 receptor β‐arrestin2‐biased ligand may be a more promising choice to treat pituitary tumours with improved therapeutic selectivity.

Hypogonadism in Male Patients with Pituitary Adenoma and Its Related Mechanism: A Review of Literature

“…The main goal of treating patients with PRL is to restore PRL to normal levels while also normalizing the testosterone levels, shrinking tumors, and improving vision [ 21 , 24 , 58 ]. Since the use of dopamine agonists for prolactinomas was first proposed in 1978, pharmacological treatment has become the preferred modality for the treatment of most prolactinomas [ 25 , 58 , 59 , 60 ].…”

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

“…It was recently shown that treatment with UNC9994 decreased the viabilities of MMQ and GH3 cells [ 23 ] at very high doses, from 3.75 μM to 30 μM. Here, we used UNC9994 at the same dose as cabergoline (100 nM) and compared their effects in the same experiment.…”

A Novel Splice Variant of BCAS1 Inhibits β-Arrestin 2 to Promote the Proliferation and Migration of Glioblastoma Cells, and This Effect Was Blocked by Maackiain

“…Studies have also indicated that nociceptin receptor (NOPr), a G protein-coupled receptor that is significantly expressed in GBM, mediates nociceptin through the β-arrestin 2/PKC/extracellular signal-regulated kinase 1/2 (Erk1/2) pathway to hinder proliferation, migration, and inflammatory signaling in lipopolysaccharide-stimulated U87 cells [ 52 ]. Furthermore, dopamine receptor type 2/β-arrestin 2 signaling can be used to inhibit Akt phosphorylation and cell proliferation in pituitary adenomas [ 53 ]. Through its nucleocytoplasmic shuttling ability, SUMOylated β-arrestin 2 enhances tumor suppressor p53 signaling by displacing Mdm2 from the nucleus to the cytoplasm [ 54 ].…”