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ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma
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 extensivel...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331066/ https://www.ncbi.nlm.nih.gov/pubmed/30666155 http://dx.doi.org/10.2147/CMAR.S187099 |
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author | Zhang, Bo Cui, Bomiao Du, Jintao Shen, Xin Wang, Kun Chen, Jiao Xiao, Liying Sun, Chongkui Li, Yan |
author_facet | Zhang, Bo Cui, Bomiao Du, Jintao Shen, Xin Wang, Kun Chen, Jiao Xiao, Liying Sun, Chongkui Li, Yan |
author_sort | Zhang, Bo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6331066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63310662019-01-21 ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma Zhang, Bo Cui, Bomiao Du, Jintao Shen, Xin Wang, Kun Chen, Jiao Xiao, Liying Sun, Chongkui Li, Yan Cancer Manag Res Original Research 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. Dove Medical Press 2019-01-09 /pmc/articles/PMC6331066/ /pubmed/30666155 http://dx.doi.org/10.2147/CMAR.S187099 Text en © 2019 Zhang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Zhang, Bo Cui, Bomiao Du, Jintao Shen, Xin Wang, Kun Chen, Jiao Xiao, Liying Sun, Chongkui Li, Yan ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title | ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title_full | ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title_fullStr | ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title_full_unstemmed | ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title_short | ATR activated by EB virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
title_sort | atr activated by eb virus facilitates chemotherapy resistance to cisplatin or 5-fluorouracil in human nasopharyngeal carcinoma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331066/ https://www.ncbi.nlm.nih.gov/pubmed/30666155 http://dx.doi.org/10.2147/CMAR.S187099 |
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