Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China.
Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Institute of Agro-bioengineering, Guizhou University, Guiyang, Guizhou Province 550025, China.
Ecotoxicol Environ Saf. 2024 May;276:116303. doi: 10.1016/j.ecoenv.2024.116303. Epub 2024 Apr 9.
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.
某些杀虫剂通过激活雌激素受体，经由基因转录来产生雌激素效应，从而被认为与乳腺癌风险增加有关。然而，雌激素受体依赖途径是否是这些化合物诱导致癌作用的唯一途径尚不清楚。本研究旨在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。采用串联质谱技术，研究了氯菊酯对细胞蛋白表达的影响，并对失调蛋白进行了基因本体论和途径功能富集分析。最后，对氯菊酯与候选靶蛋白进行了分子对接模拟，并通过基因敲低实验证实了该蛋白的功能。我们的研究结果表明，暴露于 10-40 μM 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 个上调蛋白和 34 个下调蛋白的表达失调。这些失调蛋白主要与跨膜信号转导和化学致癌作用有关。分子对接模拟表明，过度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 的敲低部分阻碍了氯菊酯诱导的细胞增殖，并通过 ERK1/2 信号通路改变增殖标志物蛋白 PCNA 和细胞周期相关蛋白 cyclin D1 的表达。这些发现为氯菊酯作为环境乳腺癌风险因素提供了新的证据，表明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。
