Metformin inhibits growth and prolactin secretion of pituitary prolactinoma cells and xenografts

Abstract

Metformin (MET) is a diabetes drug that activates AMP‐activated protein kinase (AMPK), and is suggested to have anticancer efficacy. Here, we investigated the role of AMPK signalling in prolactinoma (PRLoma), with particular respect to MET and bromocriptine (BC) as a PRLoma treatment. We analysed AMPK phosphorylation, dopamine D2 receptor (D2R), and oestrogen receptor (ER) expression in both BC‐sensitive and ‐resistant PRLoma samples; effects of the AMPK agonist MET (alone or with BC) on in vitro proliferation and apoptosis, xenograft growth and prolactin (PRL) secretion of BC‐sensitive and ‐resistant cells, and ER expression in xenografts. Some BC‐resistant PRLomas showed high D2R expression but extremely low AMPK activation. MET significantly inhibited proliferation of cultured PRLoma cells; MET + BC notably restrained their PRL secretion. MET + BC further decreased tumour growth and serum PRL levels in xenografts than BC treatment alone. ER was down‐regulated after AMPK activation in both cultured cells and xenografts. Together, we propose that the AMPK signalling pathway down‐regulates ERα and ERβ, and suppresses PRLoma growth as well as PRL secretion. Combined MET + BC is a potential treatment for PRLomas.

Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas

“…Pituitary adenomas are frequently occurring primary brain tumors that account for 15-20% of all intracranial neoplasms 1 - 3 . Prolactinomas are the most predominant type of functional pituitary adenoma, constituting ~40% of total pituitary adenomas globally 4 , 5 . Over the past decades, there have been substantial breakthroughs in the understanding and management of prolactinomas; bromocriptine is the first line treatment for prolactinomas, yet 30% of patients ultimately develop resistance 3 , 6 , 7 .…”

How treatments with endocrine and metabolic drugs influence pituitary cell function

“…AMPK phosphorylation was high in specimens from BC-sensitive tumors and significantly suppressed in BC-resistant tumors. According to the authors, these data support an involvement of AMPK in regulating tumor growth and tumor cell response to the dopamine agonist (98). Actually, it is not possible to draw a clear conclusion.…”

Clinical management of difficult to treat macroprolactinomas

“…Two recent cases of patients with BRC-resistant Prolactinomas suggest that metformine, an oral treatment commonly used in type 2 diabetes, can lead to normalization of PRL level when it is used in combination with BRC, and also to a subsequent decrease of the tumor volume after 24 months of treatment [114]. These results are supported in vitro by a synergistic inhibitory effect of metformine and BRC in combination over tumor growth and PRL secretion of xenograft models of lactotroph tumors [115].…”