{"title":"Microtubule depolymerization induces ferroptosis in neuroblastoma cells.","authors":"Mayuri Bandekar, Dulal Panda","doi":"10.1002/iub.2899","DOIUrl":null,"url":null,"abstract":"<p><p>Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":" ","pages":"1186-1198"},"PeriodicalIF":3.7000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"IUBMB Life","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/iub.2899","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.
雌莫司汀(EM)是一种在临床上获得成功的激素难治性抗前列腺癌药物,它在不同的癌细胞中表现出强大的抗增殖活性、解聚微管、阻止细胞有丝分裂并诱导细胞死亡。铁代谢改变是癌细胞的一个特征。我们利用 EM 研究了人类神经母细胞瘤(SH-SY5Y 和 IMR-32)细胞中微管解聚与诱导铁变态反应之间的合理关系。EM会降低谷胱甘肽(GSH)水平并诱导活性氧(ROS)生成。用 ROS 清除剂(N-乙酰半胱氨酸和二硫苏糖醇)预处理神经母细胞瘤细胞可降低 EM 的抗增殖作用。EM处理会增加易溶铁池(LIP)、消耗谷胱甘肽过氧化物酶4(GPX4)水平和脂质过氧化,这些都是铁变态反应的标志性特征,突出了铁变态反应的诱导作用。铁突变抑制剂(甲磺酸去铁胺和脂氧司他丁-1)可减弱 EM 的细胞毒性作用,进一步证实了铁突变诱导。长春新碱和诺考达唑也会增加神经母细胞瘤细胞的 LIP 并诱导脂质过氧化。这项研究为微管完整性与铁凋亡的耦合提供了证据。研究结果还表明,微管解聚剂可用于开发促进铁变态反应的化疗药物。
期刊介绍:
IUBMB Life is the flagship journal of the International Union of Biochemistry and Molecular Biology and is devoted to the rapid publication of the most novel and significant original research articles, reviews, and hypotheses in the broadly defined fields of biochemistry, molecular biology, cell biology, and molecular medicine.