Abstract：
Certain insecticides are known to have estrogenic effects by activating estrogen receptors through genomic transcription. This has led researchers to associate specific insecticide use with an increased breast cancer risk. However, it is unclear if estrogen receptor-dependent pathways are the only way in which these compounds induce carcinogenic effects. The objective of this study was to determine the impact of the pyrethroid insecticide permethrin on the growth of estrogen receptor negative breast cancer cells MDA-MB-231. Using tandem mass spectrometric techniques, the effect of permethrin on cellular protein expression was investigated, and gene ontology and pathway function enrichment analyses were performed on the deregulated proteins. Finally, molecular docking simulations of permethrin with the candidate target protein was performed and the functionality of the protein was confirmed through gene knockdown experiments. Our findings demonstrate that exposure to 10-40 μM permethrin for 48 h enhanced cell proliferation and cell cycle progression in MDA-MB-231. We observed deregulated expression in 83 upregulated proteins and 34 downregulated proteins due to permethrin exposure. These deregulated proteins are primarily linked to transmembrane signaling and chemical carcinogenesis. Molecular docking simulations revealed that the overexpressed transmembrane signaling protein, G protein-coupled receptor 39 (GPR39), has the potential to bind to permethrin. Knockdown of GPR39 partially impeded permethrin-induced cellular proliferation and altered the expression of proliferation marker protein PCNA and cell cycle-associated protein cyclin D1 via the ERK1/2 signaling pathway. These findings offer novel evidence for permethrin as an environmental breast cancer risk factor, displaying its potential to impact breast cancer cell proliferation via an estrogen receptor-independent pathway.
摘要：
已知某些杀虫剂通过基因组转录激活雌激素受体而具有雌激素作用。这导致研究人员将特定的杀虫剂使用与乳腺癌风险增加联系起来。然而,目前尚不清楚雌激素受体依赖性途径是否是这些化合物诱导致癌作用的唯一途径。这项研究的目的是确定拟除虫菊酯杀虫剂氯菊酯对雌激素受体阴性乳腺癌细胞MDA-MB-231生长的影响。使用串联质谱技术，研究了氯菊酯对细胞蛋白表达的影响，并对失调的蛋白质进行基因本体论和通路功能富集分析。最后,进行了氯菊酯与候选靶蛋白的分子对接模拟，并通过基因敲低实验证实了该蛋白的功能。我们的发现表明，暴露于10-40μM氯菊酯48小时可增强MDA-MB-231的细胞增殖和细胞周期进程。由于氯菊酯暴露，我们观察到83种上调蛋白和34种下调蛋白的表达失调。这些失调的蛋白质主要与跨膜信号传导和化学致癌作用有关。分子对接模拟显示过表达的跨膜信号蛋白，G蛋白偶联受体39（GPR39），有可能与氯菊酯结合.GPR39的敲除部分阻碍了氯菊酯诱导的细胞增殖，并通过ERK1/2信号通路改变了增殖标记蛋白PCNA和细胞周期相关蛋白cyclinD1的表达。这些发现为氯菊酯作为环境乳腺癌危险因素提供了新的证据，显示其通过雌激素受体非依赖性途径影响乳腺癌细胞增殖的潜力。
