Endocrine disruptors fludioxonil and fenhexamid stimulate miR-21 expression in breast cancer cells.
Endocrine disruptors fludioxonil and fenhexamid stimulate miR-21 expression in breast cancer cells.
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DOI：
10.1093/toxsci/kfs290
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Y. Teng;T. Manavalan;Chuan Hu;Svjetlana Medjakovic;A. Jungbauer;C. Klinge
中科院分区：
文献类型：
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作者：
Y. Teng;T. Manavalan;Chuan Hu;Svjetlana Medjakovic;A. Jungbauer;C. Klinge
芬甲塞明和氟菌腈是农业应用中使用的抗真菌剂，它们在水果和蔬菜中含量可测量。在工程人乳腺癌细胞的雄激素受体报告试验中，芬昔明和氟咯咯尼显示出作为抗雄激素的内分泌干扰物的活性。关于环境化学物质如何调节microRNA （miRNA）表达，我们知之甚少。本研究检测了芬昔芬和氟喹诺尼对MCF-7、T47D和MDA-MB-231人乳腺癌细胞中oncomiR miR-21表达的影响以及MCF-7细胞中miR-21的下游靶点。芬昔芬和氟咯英尼以浓度依赖性的方式刺激miR-21的表达，并降低miR-21靶蛋白Pdcd4的表达。对miR-21的反义抑制了芬昔米特和氟咯英尼对Pdcd4蛋白的升高。芬昔米德和氟咯英尼降低了miR-125b和miR-181a，显示了miRNA调控的特异性。雌激素受体拮抗剂氟维司汀、雄激素受体拮抗剂比卡鲁胺、放线菌素D和环己亚胺以及丝裂原活化蛋白激酶和磷酸肌肽3激酶途径抑制剂均可抑制miR-21的诱导。芳烃受体拮抗剂α-萘甲黄抑制芬甲塞酮的活性。芬甲塞酮和氟咯英尼不影响双氢睾酮诱导的miR-21表达。氟氧恶菌尼抑制MCF-7细胞活力，而非芬昔芬，两者都抑制雌二醇诱导的细胞增殖和降低细胞活力。综上所述，这些数据表明，芬昔芬和氟咯英尼使用相似且不同的机制来增加miR-21的表达，并具有下游抗雌激素活性。
Fenhexamid and fludioxonil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. Fenhexamid and fludioxonil showed endocrine disruptor activity as antiandrogens in an androgen receptor reporter assay in engineered human breast cancer cells. Little is known about how environmental chemicals regulate microRNA (miRNA) expression. This study examined the effect of fenhexamid and fludioxonil on the expression of the oncomiR miR-21 in MCF-7, T47D, and MDA-MB-231 human breast cancer cells and downstream targets of miR-21 in MCF-7 cells. Fenhexamid and fludioxonil stimulated miR-21 expression in a concentration-dependent manner and reduced the expression of miR-21 target Pdcd4 protein. Antisense to miR-21 blocked the increase in Pdcd4 protein by fenhexamid and fludioxonil. Fenhexamid and fludioxonil reduced miR-125b and miR-181a, demonstrating specificity of miRNA regulation. Induction of miR-21 was inhibited by the estrogen receptor antagonist fulvestrant, by androgen receptor antagonist bicalutamide, by actinomycin D and cycloheximide, and by inhibitors of the mitogen-activated protein kinases and phosphoinositide 3-kinase pathways. Fenhexamid activation was inhibited by the arylhydrocarbon receptor antagonist α-napthoflavone. Fenhexamid and fludioxonil did not affect dihydrotestosterone-induced miR-21 expression. Fludioxonil, but not fenhexamid, inhibited MCF-7 cell viability, and both inhibited estradiol-induced cell proliferation and reduced cell motility. Together these data indicate that fenhexamid and fludioxonil use similar and distinct mechanisms to increase miR-21 expression with downstream antiestrogenic activity.