ERα down-regulation plays a key role in silibinin-induced autophagy and apoptosis in human breast cancer MCF-7 cells

The estrogen receptor alpha (ER alpha) has been proven to be one of the most important therapeutic targets in breast cancer over the last 30 years. Previous studies pointed out that a natural flavonoid, silibinin, induced apoptosis in human breast cancer MCF-7 cells. In the present study we report that exposure of MCF-7 cells to silibinin led to cell death through the down-regulation of ER alpha expression. Silibinin-induced apoptosis of MCF-7 cells through up-regulation of caspase 6 due to ER alpha signalling repression was further boosted by ER alpha antagonist. Moreover, up-regulation of autophagy induced by silibinin accounted for apoptotic exacerbation, being further enhanced by ER alpha inhibition. Upon ER alpha activation, series of downstream signalling pathways can be activated. We found that silibinin reduced the expressions of Akt/mTOR and extracellular-signal-related kinase (ERK), which respectively accounted for the induction of autophagy and apoptosis. These effects were further augmented by co-treatment with ER alpha inhibitor. We conclude that the treatment with silibinin of ER alpha-positive MCF-7 cells down-regulates the expression of ER alpha, and subsequently mTOR and ERK signaling pathways, ER alpha downstream, finally resulting in induction of autophagy and apoptosis. (C) 2015 The Authors. Production and hosting by Elsevier B.V.