title: ERα down-regulation plays a key role in silibinin-induced autophagy and apoptosis in human breast cancer MCF-7 cells.
abstract: The estrogen receptor alpha (ERα) 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 ERα expression. Silibinin-induced apoptosis of MCF-7 cells through up-regulation of caspase 6 due to ERα signalling repression was further boosted by ERα antagonist. Moreover, up-regulation of autophagy induced by silibinin accounted for apoptotic exacerbation, being further enhanced by ERα inhibition. Upon ERα 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 ERα inhibitor. We conclude that the treatment with silibinin of ERα-positive MCF-7 cells down-regulates the expression of ERα, and subsequently mTOR and ERK signaling pathways, ERα downstream, finally resulting in induction of autophagy and apoptosis.
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Huai
authors.initials: H
authors.lastname: Huang
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Liu
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Linghe
authors.initials: L
authors.lastname: Zang
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Xia
authors.affiliation: Institute for Clinical and Biomedical Sciences, Kyoto 603-8072, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tashiro
authors.affiliation: Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University, Tokyo 194-8543, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: ikejimat@vip.sina.com.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D061986:MCF-7 Cells; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D012838:Silymarin; D000077385:Silybin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Autophagy; Estrogen receptor alpha (ERα); MPP dihydrochloride hydrate (MPP); Silibinin