title: Down-regulation of EBV-LMP1 radio-sensitizes nasal pharyngeal carcinoma cells via NF-κB regulated ATM expression.
abstract: BACKGROUND
  The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice.
  
  
  RESULTS
  In this study we explored the molecular mechanisms underlying the radiosensitization caused by the down-regulation of LMP1 in nasopharyngeal carcinoma. It was confirmed that LMP1 could up-regulate ATM expression in NPCs. Bioinformatic analysis of the ATM ptomoter region revealed three tentative binding sites for NF-κB. By using a specific inhibitor of NF-κB signaling and the dominant negative mutant of IkappaB, it was shown that the ATM expression in CNE1-LMP1 cells could be efficiently suppressed. Inhibition of LMP1 expression by the DNAzyme led to attenuation of the NF-κB DNA binding activity. We further showed that the silence of ATM expression by ATM-targeted siRNA could enhance the radiosensitivity in LMP1 positive NPC cells.
  
  
  CONCLUSIONS
  Together, our results indicate that ATM expression can be regulated by LMP1 via the NF-κB pathways through direct promoter binding, which resulted in the change of radiosensitivity in NPCs.
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ma
authors.forename: Lifang
authors.initials: L
authors.lastname: Yang
authors.forename: Lanbo
authors.initials: L
authors.lastname: Xiao
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.forename: Liyu
authors.initials: L
authors.lastname: Liu
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.forename: Mengyao
authors.initials: M
authors.lastname: Deng
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D002277:Carcinoma; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019295:Computational Biology; D021881:DNA, Catalytic / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007120:Immunochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy*; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D014965:X-Rays
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D018797:Cell Cycle Proteins; D021881:DNA, Catalytic; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009570:Nitriles; D034741:RNA, Small Interfering; D013450:Sulfones; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases
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