Exploiting D2R β-arrestin2-biased signaling to suppress tumor growth of pituitary adenomas.

Background and purpose Dopamine agonists (DAs) targeting dopamine receptor D2 (D2R) have been used for decades in treating pituitary adenomas. There has been little clear evidence implicating the canonical G protein signaling as the mechanism by which D2R suppresses the growth of pituitary tumors. We hypothesize that β-arrestin2-dependent signaling is the molecular mechanism dictating D2R inhibitory effects on pituitary tumor growth. Experimental approach The involvement of G protein and β-arrestin2 in bromocriptine (BRC)-mediated growth suppression in rat MMQ and GH3 tumor cells was assessed. The anti-growth effect of a β-arrestin2-biased agonist, UNC9994, was tested in cultured cells, tumor-bearing nude mice and primary cultured human pituitary adenomas. The effect of G protein signaling on tumor growth was also analyzed by using a G protein-biased agonist, MLS1547, and a Gβγ inhibitor, gallein, in vitro. Key results β-arrestin2 signaling, but not G protein pathways mediated the suppressive effect of BRC on pituitary tumor growth. UNC9994 inhibited pituitary tumor cell growth in vitro and in vivo. The suppressive function of UNC9994 was obtained by inducing intracellular reactive oxygen species (ROS) generation through downregulating mitochondrial complex I subunit NDUFA1. The effects of Gαi/o signaling and Gβγ signaling via D2R on pituitary tumor growth were cell-type-dependent. Conclusion and implications Given the very low expression of Gαi/o proteins in pituitary tumors and the complexity of the responses of pituitary tumors to G protein signaling pathways, our study reveals D2R β-arrestin2-biased ligand may be a more promising choice to treat pituitary tumors with improved therapeutic selectivity.