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

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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 ?H2AX 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.

Original languageEnglish
Pages (from-to)6323-6337
Number of pages15
JournalOncotarget
Volume5
Issue number15
DOIs
Publication statusPublished - 2014

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Chromatids
Cisplatin
Genetic Recombination
Homologous Recombination
Fanconi Anemia
Phenotype
Sister Chromatid Exchange
Genes
BRCA1 Gene
Nasopharyngeal carcinoma
S Phase
Drug Resistance
Neoplasms
DNA

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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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 ?H2AX 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.",
author = "Su, {Wen Pin} and Hsu, {Sen Huei} and Wu, {Cheng Kuei} and Chang, {Song Bin} and Lin, {Yi Ju} and Yang, {Wen Bin} and Hung, {Jan Jong} and Chiu, {Wen Tai} and Tzeng, {Shun Fen} and Tseng, {Yau Lin} and Chang, {Jang Yang} and Su, {Wu Chou} and Hungjiun Liaw",
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T1 - Chronic treatment with cisplatin induces replication-dependent sister chromatid recombination to confer cisplatin-resistant phenotype in nasopharyngeal carcinoma

AU - Su, Wen Pin

AU - Hsu, Sen Huei

AU - Wu, Cheng Kuei

AU - Chang, Song Bin

AU - Lin, Yi Ju

AU - Yang, Wen Bin

AU - Hung, Jan Jong

AU - Chiu, Wen Tai

AU - Tzeng, Shun Fen

AU - Tseng, Yau Lin

AU - Chang, Jang Yang

AU - Su, Wu Chou

AU - Liaw, Hungjiun

PY - 2014

Y1 - 2014

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