Open AccessLow concentration of formononetin promotes proliferation of estrogen receptor-positive cells through an ERα-miR-375-PTEN-ERK1/2-bcl-2 pathway
Author(s) -
Yanhong Guo,
Fengyan Tang,
Yong Wang,
Wenjun Huang,
Jing Tian,
Huiling Lü,
Xin Min,
Jian Chen
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.21923
Subject(s) - formononetin , apoptosis , mapk/erk pathway , pten , kinase , cell growth , protein kinase a , medicine , estrogen , estrogen receptor , cancer research , chemistry , pharmacology , endocrinology , pi3k/akt/mtor pathway , cancer , biochemistry , breast cancer , daidzein , genistein
A low dose of formononetin accelerates the proliferation of nasopharyngeal carcinoma cells in vitro ; however, the underlying mechanism remains unknown. Here, we investigated the molecular mechanism of formononetin in CNE2 cell proliferation. CNE2 cells were treated with 0 to 1 μM formononetin. To inhibit mitogen activated protein kinase / extracellular regulate kinase (MAPK/ERK) kinase (MEK) and microRNA (miR)-375, cells were pretreated with either PD98059 or a miR-375 inhibitor, respectively, followed by co-treatment with formononetin (0.3 μM) plus an inhibitor. Female rats were ovariectomized (OVX), and some OVX rats received formononetin or estrogen (E 2 ) injections. Sham operated animals were used as controls. Compared to control, 0.3 μM formononetin accelerated proliferation and decreased late apoptosis of CNE2 cells. However, formononetin-induced pro-growth and anti-apoptosis activity was abolished by PD98059 and the miR-375 inhibitor. In addition, 0.1 and 0.3 μM formononetin significantly increased estrogen receptor-α (ERα) and bcl-2, but decreased protein-phosphatase and tensin homologue (PTEN) protein expression, all of which was reversed by the miR-375 inhibitor. Additionally, formononetin treatment resulted in a transient upregulation of phosphorylated (p)-ERK1/2. In vivo studies indicated that formononetin significantly increased endometrium thickness and down-regulated ERα expression in OVX rats. Taken together, our study demonstrates that a low concentration of formononetin can promote growth of CNE2 cells and uterine tissues, possibly through regulating the ERα-miR-375-PTEN-ERK1/2-bcl-2 signaling pathway.