Curcumin Sensitizes Prolactinoma to Bromocriptine by Activating the ERK/EGR1 and Inhibiting AKT/GSK3β Signaling Pathway

Abstract Although bromocriptine (BRC) as first-line drugs are recommended for treating patients with prolactinoma, a minority of patients with prolactinoma resistance to BRC. Moreover, our previous study showed that the difference in drug sensitivity in BRC- treated rat prolactinoma cells, MMQ cells are more resistant to BRC, and GH3 cells are more sensitive to BRC. Curcumin (Cur) has been shown to inhibit proliferation of prolactinoma cell lines. The aim of this study is to further investigate whether Cur could enhance the growth-inhibitory effect of BRC resistance on prolactinoma cell lines and its possible mechanism. CCK-8 kit was used to test cell growth. Cell-cycle analysis and apoptosis was performed by flow cytometry. Electron microscopy was used to test autophagosome. The mRNA expression profiles were analysed using the Affymetrix Gene-Chip array. Western blotting was used to test protein expression. Our data showed that Cur enhanced the growth-inhibitory effect of BRC on GH3 and MMQ cell proliferation. BRC and Cur both induced cell apoptosis, and Cur could significantly increase the apoptosis of BRC on pituitary adenoma cells through the ERK/EGR1 signaling pathway. Moreover, Cur could enhance the autophagic cell death (ACD) of BRC on tumor cell by inhibiting the AKT/GSK3β signaling pathway. The same results were confirmed in vivo study. Taken together, Cur sensitizes rat pituitary adenoma cell to BRC by activating the ERK/EGR1 and inhibiting AKT/GSK3β signaling pathway.