title: Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: rohjl@amc.seoul.kr.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Daiha
authors.initials: D
authors.lastname: Shin
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003553:Cystine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005973:Glutamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D010879:Piperazines; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; C477224:erastin; D005973:Glutamine; D012460:Sulfasalazine; D003553:Cystine; D005978:Glutathione; D002945:Cisplatin
keywords: Cisplatin resistance; Cystine/glutamate antiporter; Ferroptosis; Head and neck cancer; Lipid reactive oxygen species