Low-concentration BPF induced cell biological responses by the ERα and GPER1-mediated signaling pathways in MCF-7 breast cancer cells
Low-concentration BPF induced cell biological responses by the ERα and GPER1-mediated signaling pathways in MCF-7 breast cancer cells
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低浓度 BPF 通过 ER α 和 GPER1 介导的信号通路在 MCF-7 乳腺癌细胞中诱导细胞生物反应
DOI：
10.1016/j.ecoenv.2018.08.102
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发表时间：
2018-12-15
影响因子：
6.8
通讯作者：
Feng, Chenglian
中科院分区：
文献类型：
--
作者：
Lei, Bingli;Huang, Yaoyao;Feng, Chenglian
双酚F（BPF）是双酚A（BPA）的替代品之一，可通过核雌激素受体ER α（雌激素受体α）途径诱导人乳腺癌MCF-7细胞增殖。然而，膜雌激素受体GPER 1（G蛋白偶联受体1）介导的信号通路在BPF引起的MCF-7细胞增殖中的作用尚不清楚。从细胞增殖、细胞内钙离子（Ca 2+）波动和活性氧（ROS）产生等方面评价BPF对MCF-7细胞的影响。通过检测ER α和GPER 1调节的PI 3 K/PK B或AKT（磷脂酰肌醇3-激酶/蛋白激酶B）和ERK 1/2（细胞外信号调节激酶1/2）信号的激活，研究低剂量BPF对细胞反应的分子机制。在0.01-1 μ M时，BPF显著促进细胞增殖，并升高细胞内ROS和Ca ~（2+）水平。在这些浓度下，BPF还显著上调ER α、GPER 1、c-myc和细胞周期蛋白D的蛋白表达以及PKB和ERK 1/2的磷酸化。特异性信号抑制剂降低PKB和ERK 1/2磷酸化，减弱BPF的作用。GPER 1的沉默也显著降低了BPF诱导的细胞增殖。上述结果表明，低剂量BPF激活GPER 1-PI 3 K/PKB和ERK 1/2信号，可调节MCF-7细胞的反应，ER α也影响BPF对细胞的作用。本研究提出了一种新的机制，BPF在癌细胞中发挥相关的雌激素作用，并强调了使用BPF作为BPA替代品的潜在风险。
Bisphenol F (BPF), one of the alternatives to bisphenol A (BPA), can induce proliferation through the nuclear estrogen receptor ER alpha (estrogen receptor alpha) pathway in human breast cancer MCF-7 cells. However, the roles of membrane estrogen receptor GPER1 (G-protein-coupled receptor 1)-mediated signaling pathways in MCF-7 cell proliferation caused by BPF are unclear. The influence of BPF on MCF-7 cells was evaluated in terms of cell proliferation, intracellular calcium (Ca2+) fluctuations, and reactive oxygen species (ROS) generation. The molecular mechanisms of the cellular responses to low doses of BPF were studied through detecting the activations of ER alpha and GPER1-regulated PI3K/PKB or AKT (phosphatidylinotidol 3-kinase/protein kinase B) and ERK1/2 (extracellular-signal-regulated kinase 1/2) signals. At 0.01-1 mu M, BPF significantly promoted cell proliferation and elevated the levels of intracellular ROS and Ca2+. At these concentrations, BPF also significantly upregulated protein expressions of ER alpha, GPER1, c-myc, and cyclin D and phosphorylations of PKB and ERK1/2. Specific signal inhibitors decreased PKB and ERK1/2 phosphorylations and attenuated the effects of BPF. Silencing of GPER1 also significantly decreased BPF-induced cell proliferation. These results indicate that activating the GPER1-PI3K/PKB and ERK1/2 signals by low doses of BPF can regulate the response of MCF-7 cells and that ERa also influences the effects of exposure to BPF on the cells. The present study suggests a new mechanism by which BPF exerts relevant estrogenic action in cancer cells and also highlights the potential risks in using BPF as an alternative to BPA.