Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer
Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer
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DOI：
10.1016/j.canlet.2016.07.035
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发表时间：
2016-10-10
期刊：
影响因子：
9.7
通讯作者：
Shin, Daiha
中科院分区：
文献类型：
--
作者：
Roh, Jong-Lyel;Kim, Eun Hye;Shin, Daiha
抑制与铁下垂相关的关键分子，胱氨酸/谷氨酸逆向转运体和谷胱甘肽过氧化物酶，可能会导致化疗/放射耐药癌细胞的根除。本研究探讨了铁性下垂能否克服头颈癌(HNC)对顺铂的耐药性。使用3个顺铂耐药的HNC细胞系(AMC-HN3R、-HN4R和-HN9R)及其亲本。通过测定存活率、死亡率、活性氧产生、蛋白表达和临床前小鼠移植瘤模型，评价半胱氨酸和谷氨酸的改变以及对半胱氨酸/谷氨酸逆向转运体的药理和遗传抑制的影响。不含半胱氨酸或谷氨酰胺过量的条件培养液诱导顺铂敏感和耐药的HNC细胞铁性下垂，而对坏死和凋亡标志物没有任何明显的变化。半胱氨酸/谷氨酸逆向转运体抑制剂Erastin和柳氮磺胺吡啶可抑制HNC细胞的生长和脂质过氧化产物的积累，从而导致铁下垂。用siRNA或shRNA处理基因沉默的半胱氨酸/谷氨酸逆向转运体也能诱导耐药HNC细胞有效的铁链状细胞死亡，并增强耐药HNC细胞对顺铂的细胞毒作用。在体外和体内，半胱氨酸/谷氨酸逆向转运体的药理和遗传抑制显著地使耐药的HNC细胞对顺铂敏感。药物和遗传抑制半胱氨酸/谷氨酸逆向转运蛋白通过诱导铁下垂克服顺铂耐药的HNC细胞。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R,-HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and-resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.