title: Chronic treatment with cisplatin induces replication-dependent sister chromatid recombination to confer cisplatin-resistant phenotype in nasopharyngeal carcinoma.
abstract: Cisplatin can cause intrastrand and interstrand crosslinks between purine bases and is a chemotherapeutic drug widely used to treat cancer. However, the major barrier to the efficacy of the treatment is drug resistance. Homologous recombination (HR) plays a central role in restoring stalled forks caused by DNA lesions. Here, we report that chronic treatment with cisplatin induces HR to confer cisplatin resistance in nasopharyngeal carcinoma (NPC) cells. A high frequency of sister chromatid exchanges (SCE) occurs in the cisplatin-resistant NPC cells. In addition, several genes in the Fanconi anemia (FA) and template switching (TS) pathways show elevated expression. Significantly, depletion of HR gene BRCA1, TS gene UBC13, or FA gene FANCD2 suppresses SCE and causes cells to accumulate in the S phase, concomitantly with high γH2AX foci formation in the presence of low-dose cisplatin. Consistent with this result, depletion of several genes in the HR, TS, or FA pathway sensitizes the cisplatin-resistant NPC cells to cisplatin. Our results suggest that the enhanced HR, in coordination with the FA and TS pathways, underlies the cisplatin resistance. Targeting the HR, TS, or FA pathways could be a potential therapeutic strategy for treating cisplatin-resistant cancer.
authors: Departments of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University; Graduate Institutes of Clinical Medicine, College of Medicine, National Cheng Kung University.
authors: Wen-Pin
authors: WP
authors: Su
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan; These authors contributed equally to this work.
authors: Sen-Huei
authors: SH
authors: Hsu
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan; These authors contributed equally to this work.
authors: Cheng-Kuei
authors: CK
authors: Wu
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan.
authors: Song-Bin
authors: SB
authors: Chang
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan.
authors: Yi-Ju
authors: YJ
authors: Lin
authors: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University.
authors: Wen-Bin
authors: WB
authors: Yang
authors: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University.
authors: Jan-Jong
authors: JJ
authors: Hung
authors: Department of Biomedical Engineering, National Cheng Kung University.
authors: Wen-Tai
authors: WT
authors: Chiu
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan.
authors: Shun-Fen
authors: SF
authors: Tzeng
authors: Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University.
authors: Yau-Lin
authors: YL
authors: Tseng
authors: Departments of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University; National Institute of Cancer Research, National Health Research Institutes, Taiwan.
authors: Jang-Yang
authors: JY
authors: Chang
authors: Cancer Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University.
authors: Wu-Chou
authors: WC
authors: Su
authors: Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan.
authors: Hungjiun
authors: H
authors: Liaw
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011995:Recombination, Genetic / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin