Lei Bingli, Tang Qianqian, Sun Su, Zhang Xiaolan, Huang Yaoyao, Xu Lanbing
Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, PR China; Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Guangzhou Key Laboratory Environmental Catalysis and Pollution Control, School of Environmental Science and Engineering, Institute of Environmental Health and Pollution Control, Guangdong University of Technology, Guangzhou, 510006, PR China.
Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, PR China.
Environ Pollut. 2021 Apr 15;275:116636. doi: 10.1016/j.envpol.2021.116636. Epub 2021 Feb 3.
Tetrachlorobisphenol A (TCBPA), a chlorinated derivative of bisphenol A, is an endocrine disruptor based on interaction with nuclear estrogen receptor alpha (ERα). However, there is only limited data on the mechanisms through which TCBPA-associated estrogenic activity is related to the membrane G protein-coupled estrogen receptor (GPER) pathway. In this study, three human breast cancer cell lines-MCF-7, SKBR3, and MDA-MB-231 cells were used to evaluate whether, as well as how, TCBPA at concentration range of 0.001-50 μM affect cell proliferation. The role of GPER signaling in TCBPA-induced cell proliferation was studied by analyzing the protein expression and mRNA levels of relevant signal targets. The results showed that low concentrations of TCBPA significantly induced the proliferation of MCF-7, SKBR3, and MDA-MB-231 cells, with MCF-7 cells being the most sensitive to TCBPA exposure. Low-concentration TCBPA also upregulated the expression of GPER, CyclinD1, c-Myc, and c-Fos proteins, as well as increased the phosphorylation of extracellular signal-regulated-kinase 1/2 (Erk1/2) and protein kinase B (Akt). Additionally, the mRNA levels of genes associated with estrogen signaling pathways also increased upon exposure to TCBPA. However, the phosphorylation of Erk1/2 and Akt decreased when the cells were treated with GPER inhibitor G15 and phosphatidylinositide 3-kinase (PI3K) inhibitor wortmannin (WM) prior to TCBPA exposure. Besides, the increased proliferation of breast cancer cells induced by TCBPA were also inhibited. In ERα-positive MCF-7 cells, TCBPA also upregulated ERα expression, and ERα was found to interact with GPER-mediated signaling. The results indicate that GPER activates the PI3K/Akt and Erk1/2 signal cascades to drive the cell proliferation observed for low concentrations of TCBPA. The presented results suggest a new mechanism by which TCBPA exerts estrogenic action in breast cancer cells, namely, GPER signaling in an ERα-independent manner, and also highlights the potential risks to human health of the usage of TCBPA.
四氯双酚A（TCBPA）是双酚A的一种氯化衍生物，基于其与核雌激素受体α（ERα）的相互作用，它是一种内分泌干扰物。然而，关于TCBPA相关雌激素活性与膜G蛋白偶联雌激素受体（GPER）途径相关的机制的数据有限。在本研究中，使用三种人乳腺癌细胞系——MCF-7、SKBR3和MDA-MB-231细胞，来评估浓度范围为0.001-50μM的TCBPA是否以及如何影响细胞增殖。通过分析相关信号靶点的蛋白表达和mRNA水平，研究了GPER信号在TCBPA诱导的细胞增殖中的作用。结果表明，低浓度的TCBPA显著诱导了MCF-7、SKBR3和MDA-MB-231细胞的增殖，其中MCF-7细胞对TCBPA暴露最为敏感。低浓度的TCBPA还上调了GPER、细胞周期蛋白D1、c-Myc和c-Fos蛋白的表达，并增加了细胞外信号调节激酶1/2（Erk1/2）和蛋白激酶B（Akt）的磷酸化。此外，暴露于TCBPA后，与雌激素信号通路相关的基因的mRNA水平也增加。然而，在TCBPA暴露前用GPER抑制剂G-15和磷脂酰肌醇3-激酶（PI3K）抑制剂渥曼青霉素（WM）处理细胞后，Erk1/2和Akt的磷酸化降低。此外，TCBPA诱导的乳腺癌细胞增殖增加也受到抑制。在ERα阳性的MCF-7细胞中，TCBPA还上调了ERα的表达，并且发现ERα与GPER介导的信号相互作用。结果表明，GPER激活PI3K/Akt和Erk1/2信号级联反应，以驱动低浓度TCBPA所观察到的细胞增殖。所呈现的结果表明了TCBPA在乳腺癌细胞中发挥雌激素作用的一种新机制，即GPER以不依赖ERα的方式发出信号，并且还突出了使用TCBPA对人类健康的潜在风险。
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