Chronic treatment with cisplatin induces replication-dependent sister chromatid recombination to confer cisplatin-resistant phenotype in nasopharyngeal carcinoma

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 ca...

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Published in:Oncotarget 2014-08, Vol.5 (15), p.6323-6337
Main Authors: Su, Wen-Pin, Hsu, Sen-Huei, Wu, Cheng-Kuei, Chang, Song-Bin, Lin, Yi-Ju, Yang, Wen-Bin, Hung, Jan-Jong, Chiu, Wen-Tai, Tzeng, Shun-Fen, Tseng, Yau-Lin, Chang, Jang-Yang, Su, Wu-Chou, Liaw, Hungjiun
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Carcinoma
Cell Line, Tumor
Cisplatin - pharmacology
Humans
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms - drug therapy
Nasopharyngeal Neoplasms - genetics
Nasopharyngeal Neoplasms - metabolism
Phenotype
Recombination, Genetic - drug effects
Research Paper
Sister Chromatid Exchange - drug effects
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2210