Exploiting D 2 receptor β‐arrestin2‐biased signalling to suppress tumour growth of pituitary adenomas

Background and Purpose Dopamine agonists targeting D 2 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 D 2 receptor suppresses the growth of pituitary tumours. We hypothesize that β‐arrestin2‐dependent signalling is the molecular mechanism dictating D 2 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 D 2 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 D 2 receptor β‐arrestin2‐biased ligand may be a more promising choice to treat pituitary tumours with improved therapeutic selectivity.