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British Journal of Pharmacology

British Journal of Pharmacology

IF: 6.8
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Exploiting D 2 receptor β‐arrestin2‐biased signalling to suppress tumour growth of pituitary adenomas

Published:26 April 2021 DOI: 10.1111/bph.15504
Zhoubin Tan, Zhuowei Lei, Zisheng Yan, Xuetao Ji, Xiaoai Chang, Zhi Cai, Liang Lu, Yiwei Qi, Xiumei Yin, Xiao Han, Ting Lei

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.

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Materials
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GALLEIN 2103-64-2 C20H12O7 144 suppliers $9.00-$530.00
GALLEIN 2103-64-2 C20H12O7 144 suppliers $9.00-$530.00
GALLEIN 2103-64-2 C20H12O7 144 suppliers $9.00-$530.00
GALLEIN 2103-64-2 C20H12O7 144 suppliers $9.00-$530.00

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