{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:52:42Z","timestamp":1790913162348,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81602202"],"award-info":[{"award-number":["81602202"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Dopamine agonists targeting D<jats:sub>2<\/jats:sub> 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<jats:sub>2<\/jats:sub> receptor suppresses the growth of pituitary tumours. We hypothesize that \u03b2\u2010arrestin2\u2010dependent signalling is the molecular mechanism dictating D<jats:sub>2<\/jats:sub> receptor inhibitory effects on pituitary tumour growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The involvement of G protein and \u03b2\u2010arrestin2 in bromocriptine\u2010mediated growth suppression in rat MMQ and GH3 tumour cells was assessed. The anti\u2010growth effect of a \u03b2\u2010arrestin2\u2010biased agonist, UNC9994, was tested in cultured cells, tumour\u2010bearing 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\u2010biased agonist, MLS1547, and a G\u03b2\u03b3 inhibitor, gallein, <jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>\u03b2\u2010arrestin2 signalling but not G protein pathways mediated the suppressive effect of bromocriptine on pituitary tumour growth. UNC9994 inhibited pituitary tumour cell growth <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. The suppressive function of UNC9994 was obtained by inducing intracellular reactive oxygen species generation through downregulating mitochondrial complex I subunit NDUFA1. The effects of G\u03b1i\/o signalling and G\u03b2\u03b3 signalling via D<jats:sub>2<\/jats:sub> receptor on pituitary tumour growth were cell\u2010type\u2010dependent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Given the very low expression of G\u03b1i\/o proteins in pituitary tumours and the complexity of the responses of pituitary tumours to G protein signalling pathways, our study reveals D<jats:sub>2<\/jats:sub> receptor \u03b2\u2010arrestin2\u2010biased ligand may be a more promising choice to treat pituitary tumours with improved therapeutic selectivity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15504","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T03:19:35Z","timestamp":1619493575000},"page":"3570-3586","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exploiting D<sub>2<\/sub> receptor \u03b2\u2010arrestin2\u2010biased signalling to suppress tumour growth of pituitary adenomas"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-8974","authenticated-orcid":false,"given":"Zhoubin","family":"Tan","sequence":"first","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuowei","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zisheng","family":"Yan","sequence":"additional","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuetao","family":"Ji","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoai","family":"Chang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Cai","sequence":"additional","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lu","sequence":"additional","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Qi","sequence":"additional","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiumei","family":"Yin","sequence":"additional","affiliation":[{"name":"Intensive Care Unit Nanjing Jiangning Hospital of Jiangsu Province  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory of Human Functional Genomics of Jiangsu Province Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Lei","sequence":"additional","affiliation":[{"name":"Sino\u2010German Neuro\u2010Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyy059"},{"issue":"1","key":"e_1_2_12_3_1","first-page":"S21","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: G protein\u2010coupled receptors","volume":"176","author":"Alexander S. 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