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ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma

Authors Zhang B, Cui B, Du J, Shen X, Wang K, Chen J, Xiao L, Sun C, Li Y

Received 10 September 2018

Accepted for publication 19 November 2018

Published 9 January 2019 Volume 2019:11 Pages 573—585

DOI https://doi.org/10.2147/CMAR.S187099

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 3

Editor who approved publication: Dr Kenan Onel


Bo Zhang,1,* Bomiao Cui,1,* Jintao Du,2 Xin Shen,1 Kun Wang,1 Jiao Chen,1 Liying Xiao,1 Chongkui Sun,1 Yan Li1

1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China; 2Department of Otorhinolaryngology–Head and Neck Surgery, West China Hospital, Chengdu 610041, Sichuan, China

*These authors contributed equally to this work

Purpose: Epstein–Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC) and increases the chemotherapy resistance of tumor cells. Although the mechanism by which EBV manipulates ataxia telangiectasia mutation (ATM)-mediated DNA damage response in NPC has been extensively studied, the relationship between ATR (ATM and Rad-3 related) and EBV infection is largely unexplored, and also the role of ATR in chemotherapy resistance in EBV-positive NPC has not been specifically reported.
Materials and methods: Levels of γ-H2AX, latent membrane protein 1 (LMP1), and EBV-encoded RNA in clinical NPC and nasopharyngeal inflammation (NPI) specimens were examined using immunohistochemistry and in situ hybridization. The effects of EBV infection, chemotherapy drugs cisplatin (CDDP) and 5-fluorouracil (5-FU) treatment, and ATR silencing were assessed in NPC cells in vitro using immunofluorescence, Western blot, and flow cytometry.
Results: A notable increase of γ-H2AX expression was examined in the EBV-positive NPC clinical specimens. Additionally, we observed that the phosphorylation of ATR/checkpoint kinase 1 (CHK1) pathway protein was gradually activated along with the duration of EBV exposure in NPC cell lines, which was obviously inhibited after ATR depletion. Moreover, EBV infection promoted the resistance of NPC cells to CDDP and 5-FU, whereas the chemosensitivity of cells was significantly enhanced following ATR knockdown. Furthermore, ATR depletion caused both S-phase cell arrest and apoptosis, enhanced p53 phosphorylation, and impaired the formation of Rad51.
Conclusion: Our data suggest that EBV activation of ATR-mediated DNA damage response might result in chemotherapy resistance to CDDP and 5-FU in NPC. Accordingly, ATR knockdown may serve as an effective treatment strategy for chemotherapy-resistant, EBV-positive NPC.

Keywords: ATR, EBV, NPC, chemotherapy resistance, cisplatin, 5-fluorouracil, ATRi, CNE1, Rad51, p53

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