Chronic treatment with cisplatin induces replication-dependent sister chromatid recombination to confer cisplatin-resistant phenotype in nasopharyngeal carcinoma
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Wen-Pin Su1,2, Sen-Huei Hsu3,*, Cheng-Kuei Wu3,*, Song-Bin Chang3, Yi-Ju Lin3, Wen-Bin Yang4, Jan-Jong Hung4, Wen-Tai Chiu 5, Shun-Fen Tzeng3, Yau-Lin Tseng6, Jang-Yang Chang1,7, Wu-Chou Su8, Hungjiun Liaw3
1 Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
2 Graduate Institutes of Clinical Medicine, College of Medicine, National Cheng Kung University
3 Department of Life Sciences, National Cheng Kung University, No.1 University Road, Tainan City 701, Taiwan
4 Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University
5 Department of Biomedical Engineering, National Cheng Kung University
6 Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
7 National Institute of Cancer Research, National Health Research Institutes, Taiwan
8 Cancer Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University
* These authors contributed equally to this work
Hungjiun Liaw, email:
Wu-Chou Su, email:
Keywords: cisplatin, cisplatin resistant phenotype, homologous recombination, template-switching, Fanconi anemia, nasopharyngeal carcinoma
Received: June 07, 2014 Accepted: July 11, 2014 Published: July 12, 2014
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.
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