Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer

被引:314
作者
Roh, Jong-Lyel [1 ]
Kim, Eun Hye [1 ]
Jang, Hye Jin [1 ]
Park, Jin Young [1 ]
Shin, Daiha [1 ]
机构
[1] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Otolaryngol, Seoul, South Korea
基金
新加坡国家研究基金会;
关键词
Head and neck cancer; Ferroptosis; Cystine/glutamate antiporter; Lipid reactive oxygen species; Cisplatin resistance; CYSTINE TRANSPORT; TUMOR-REGRESSION; SYSTEM XC(-); XCT; GLUTATHIONE; ESTABLISHMENT; RADIOTHERAPY; SENSITIVITY; INHIBITION; ANTIPORTER;
D O I
10.1016/j.canlet.2016.07.035
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:96 / 103
页数:8
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