Molecular mechanism of bisphenol AF-induced proliferation of breast cancer cells
LU Fen1, TANG Qian-qian2, LOU Shu-fang1, LEI Bing-li2
1. School of Nursing, Shangqiu Medical College, Shangqiu 476000, China; 2. Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China
Abstract:The effects of different concentrations of bisphenol AF (BPAF) on cell viability, cell cycle and apoptosis in MCF-7 In the study, breast cancer cells was evaluated. To evaluate cell proliferation mechanism, the novel estrogen membrane receptor G protein-coupled receptor 1 (GPER1)-mediated phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways were used as targets. The effects of BPAF on the mRNA levels of related targets associated with PI3K/Akt and ERK1/2 signaling pathways were investigated and their roles in low concentration BPAF-induced breast cancer cell proliferation were analyzed. The results showed that low concentrations of BPAF (0.001~1μmol/L) significantly induced the cell proliferation, increased the proportion of S-phase cells and up-regulated mRNA levels of target genes in MCF-7cells. At high concentrations (>10 μmol/L), BPAF significantly inhibited cell viability and induced cell apoptosis. In addition, by using specific signal inhibitors, it was found that GPER1activated PI3K/Akt and ERK1/2 signaling pathways in mRNA level and activation of PI3K/Akt and ERK1/2 signaling pathways via GPER1 may be a key mechanism of BPAF-induced MCF-7 cell proliferation. ERα also plays an important role in this process.
卢芬, 汤倩倩, 娄淑芳, 雷炳莉. 双酚AF诱导乳腺癌细胞增殖的分子机制[J]. 中国环境科学, 2021, 41(12): 5896-5903.
LU Fen, TANG Qian-qian, LOU Shu-fang, LEI Bing-li. Molecular mechanism of bisphenol AF-induced proliferation of breast cancer cells. CHINA ENVIRONMENTAL SCIENCECE, 2021, 41(12): 5896-5903.
Liu Y, Zhang S, Song N, et al. Occurrence, distribution and sources of bisphenol analogues in a shallow Chinese freshwater lake (Taihu Lake): implications for ecological and human health risk[J]. Science of the Total Environment, 2017,599-600:1090-1098.
[2]
Siracusa J S, Yin L, Measel E, et al. Effects of bisphenol A and its analogs on reproductive health: A mini review[J]. Reproductive Toxicology, 2018,79:96-123.
[3]
Liao C Y, Liu F, Guo Y, et al. Occurrence of eight bisphenol analogues in indoor dust from the United States and several Asian countries: implications for human exposure[J]. Environmental Science and Technology, 2012,46:9138-9145.
[4]
Huang Z, Zhao J L, Yang Y Y, et al. Occurrence, mass loads and risks of bisphenol analogues in the Pearl River Delta region, South China: Urban rainfall runoff as a potential source for receiving rivers[J]. Environmental Pollution, 2020,263:114361.
[5]
Wang H, Liu Z H, Tang Z, et al. Bisphenol analogues in Chinese bottled water: Quantification and potential risk analysis[J]. Science of the Total Environment, 2020,713:136583.
[6]
Akhbarizadeh R, Moore F, Monteiro C, et al. Occurrence, trophic transfer, and health risk assessment of bisphenol analogues in seafood from the Persian Gulf[J]. Marine Pollution Bulletin, 2020,154:111036.
[7]
Wang Q, Chen M, Shan G Q, et al. Bioaccumulation and biomagnification of emerging bisphenol analogues in aquatic organisms from Taihu Lake, China[J]. Science of the Total Environment, 2017,598:814-820.
[8]
Jin H B, Xie J H, Mao LL, et al. Bisphenol analogue concentrations in human breast milk and their associations with postnatal infant growth[J]. Environmental Pollution, 2020,259:11379.
[9]
Li A J, Zhuang T F, Shi W, et al. Serum concentration of bisphenol analogues in pregnant women[J]. Science of the Total Environment, 2020,707:136100.
[10]
Maruyama K, Nakamura M, Tomoshige S, et al. Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERα-selective antagonist[J]. Bioorganic & Medicinal Chemistry Letters, 2013,23:4031-4036.
[11]
Fic A, Žegura B, Gramec D, et al. Estrogenic and androgenic activities of TBBPA and TBMEPH, metabolites of novel brominated flame retardants, and selected bisphenols, using the XenoScreen XL YES/ YAS assay[J]. Chemosphere, 2014,112:362-369.
[12]
Li Y, Burns K A, Arao Y, et al. Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and zearalenone through estrogen receptor α and β in vitro[J]. Environmental Health Perspectives, 2012,120:1029-1035.
[13]
Song M Y, Liang D, Liang Y, et al. Assessing developmental toxicity and estrogenic activity of halogenated bisphenol A on zebrafish (Danio rerio)[J]. Chemosphere, 2014,112:75-281.
[14]
Cao L Y, Ren X M, Li C H, et al. Bisphenol AF and bisphenol B exert higher estrogenic effects than bisphenol A via G-protein-coupled estrogen receptor pathway[J]. Environmental Science Technology, 2017,51:11423-11430.
[15]
Kwon B, Kho Y L, Kim P G, et al. Thyroid endocrine disruption in male zebrafish following exposure to binary mixture of bisphenol AF and sulfamethoxazole[J]. Environmental Toxicology and Pharmacology, 2016,48:168-174.
[16]
Sui Y P, Ai N, Park S H, et al. Bisphenol A and its analogues activate human pregnane X receptor[J]. Environmental Health Perspectives, 2012,120:399-405.
[17]
Lei B L, Xu J, Peng W, et al. In vitro profiling of toxicity and endocrine disrupting effects of bisphenol analogues by employing MCF-7cells and two-hybrid yeast bioassay[J]. Environmental Toxicology, 2017,32(1):278-289.
[18]
Lee S, Kim Y K, Shim T Y, et al. Neurotoxic effects of bisphenol AF on calcium-induced ROS and MAPKs[J]. Neurotoxicity Research, 2013,23:249-259.
[19]
Li Y, Perera L, Coons L A, et al. Differential in vitro biological action, coregulator interactions, and molecular dynamic analysis of bisphenol A (BPA), BPAF, and BPS ligand-ERα complexes[J]. Environmental Health Perspectives, 2018,126(1):doi.org/10.1289/EHP2505.
[20]
Matsushima A, Liu X, Okada H, et al. Bisphenol AF is a full agonist for the estrogen receptor ERα but a highly specific antagonist for Erβ[J]. Environmental Health Perspectives, 2010,118:1267-1272.
[21]
Romano S N, Gorelick D A. Crosstalk between nuclear and G protein-coupled estrogen receptors[J]. General and Comparative Endocrinology, 2018,261:190-197.
[22]
Barton M, Filardo E J, Lolaits S J, et al. Twenty years of the G protein-coupled estrogen receptor GPER: Historical and personal perspectives[J]. Journal of Steroid Biochemistry and Molecular Biology, 2018,176:4-15.
[23]
Lei B L, Sun S, Zhang X L, et al. Bisphenol AF exerts estrogenic activity in MCF-7cells through activation of Erk and PI3K/Akt signals via GPER signaling pathway[J]. Chemosphere, 2019,220:362-370.
[24]
Feng Y X, Yin J, Jiao Z H, et al. Bisphenol AF may cause testosterone reduction by directly affecting testis function in adult male rats[J]. Toxicology Letters, 2012,211:201-209.
[25]
Pupo M, Pisano A, LAppano R, et al. Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts[J]. Environmental Health Perspectives, 2012,120:1177-1187.
[26]
Leik B L, Peng W, Xu G, et al. Activation of G protein-coupled receptor 30by thiodiphenol promotes proliferation of estrogen receptor α-positive breast cancer cells[J]. Chemosphere, 2017,169:204-211.
[27]
隋佳琪,谢鲲鹏,谢明杰.乳腺癌相关的细胞内信号通路[J]. 中国生物化学与分子生物学报, 2015,31:20-27. Sui J Q, Xie K P, Xie M J. Cellular signaling pathways in breast cancer[J]. Chinese Journal of Biochemistry and Molecular Biology, 2015,31:20-27.
[28]
Garcia M A,Pena D,Alvarez L,et al. Hexachlorobenzene induces cell proliferation and IGF-I signaling pathway in an estrogen receptor a-dependent manner in MCF-7breast cancer cell line[J]. Toxicology Letters, 2010,192:195-205.
[29]
Sengupta S, Obiorah I, Maximov P Y, et al. Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells[J]. British Journal of Pharmacology, 2013,169:167-178.
[30]
Ishibashi Y, Ohtsu H, Ikemura M, et al. Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer[J]. Scientific Reports, 2017,7(1):4846.
[31]
Du G Q, Zhou L, Chen X Y, et al. The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells[J]. Biochemical and Biophysical Research Communications, 2012,420:343-349.
[32]
陈花,马海蓉.乳腺癌治疗新靶点GPER1研究进展[J]. 中华肿瘤防治杂志, 2014,21:959-964. Chen H, Ma H R. Advances on the new target GPER1for therapy of breast cancer[J]. Chinese Journal of Cancer Prevention and Treatment, 2014,21:959-964.
[33]
Wei Y, Zhang Z, Liao H, et al. Nuclear estrogen receptor-mediated Notch signaling and GPR30-mediated PI3K/AKT signaling in the regulation of endometrial cancer proliferation[J]. Oncology Reports, 2012,27:504-510.
[34]
Deng W J,Wang Y Y, Zhao S,et al. MICAL1facilitates breast cancer cell proliferation via ROS-sensitive ERK/cyclin D pathway[J]. Journal of Cellular and Molecular Medicine, 2018,22(6):3108-3118.
[35]
Pfeifer D, Chuang Y M, Hu M C. Effects of low-dose bisphenol A on DNA damaged proliferation of breast cells: the role of c-Myc[J]. Environmental Health Perspectives, 2015,123(12):1271-1279.
[36]
Park M A, Hwang K A, Lee H R, et al. Cell growth of BG-1ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromoyclododecane via upregulation of the cyclin D and cyclin-dependent kinase-4genes[J]. Molecular Medicine Reports, 2012,5(3):761-766.
[37]
Tu G,Yu T H. GPER mediates enhanced cell viability and motility via non-genomic signaling induced by 17beta-estradiol in triple-negative breast cancer cells.[J] Journal of Steroid Biochemistry and Molecular Biology, 2014,143:392-403.
[38]
Sheng Z G, Zhu B Z. Low concentrations of bisphenol a induce mouse spermatogonia cell proliferation by a protein-coupled receptor 30 and estrogen receptor-alpha[J]. Environmental Health Perspectives, 2011,119(12):1775-1780.
[39]
Silva E, Kabil A, Kortenamp A. Cross-talk between non-genomic and genomic signaling pathways-distinct effect profiles of environmental estrogens[J]. Toxicology and Applied Pharmacology, 2010,245(2):160-170.
[40]
Ge L C, Chen Z J, Liu H Y, et al. Signaling related with biphasic effects of bisphenol A (BPA) on Sertoli cell proliferation: A comparative proteomic analysis[J]. Biochimica et Biophysica Acta, 2014,1840:2663-2673.