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

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.