title: ERβ up-regulation was involved in silibinin-induced growth inhibition of human breast cancer MCF-7 cells.
abstract: We previously reported that silibinin induced a loss of cell viability in breast cancer (MCF-7) cells by ERα down-regulation. But whether this cytotoxicity depends on another estrogen receptor, ERβ, has yet to be elucidated. Therefore, we sought to explore the effects of ERβ modulation on cell viability by using an ERβ-selective agonist (Diarylprepionitrile, DPN) and an antagonist (PHTPP). Our data demonstrated that ERβ served as a growth suppressor in MCF-7 cells, and the incubation of silibinin, elevated ERβ expression, resulting in the tumor growth inhibition. The cytotoxic effect of silibinin was diminished by PHTPP and enhanced by DPN. Silencing of ERβ by siRNA confirmed these results. Apoptotic cascades, including the sequential activation of caspase-9 and -6, and finally the cleavage of caspase substrates, PARP and ICAD, caused by treatment with silibinin, were all repressed by PHTPP pre-treatment but exacerbated by DPN. Unlike ERα, ERβ did not involve autophagic process in the regulation, since neither autophagic inhibitor (3-MA) nor the inducer (rapamycin) affected the cell survival rates regardless ERβ activity. Taken together, silibinin induced apoptosis through mitochondrial pathway by up-regulating ERβ pathways in MCF-7 cells without the involvement of autophagy.
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: 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: 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: 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: 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: Toshihiko
authors.initials: T
authors.lastname: Hayashi
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: xmywd@vip.sina.com.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Xia
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*; D049109:Cell Proliferation / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D047629:Estrogen Receptor beta; D012838:Silymarin; D000077385:Silybin
keywords: Apoptosis; Autophagy; ER-β agonist (DPN); ER-β antagonist (PHTPP); Estrogen receptor beta (ERβ); Silibinin