Abstract
BackgroundThe 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.ResultsIn 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.ConclusionsTogether, 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.
Highlights
Radio-resistance has been one of the impediments in clinical settings for effective cancer therapy, which is thought to be associated with multiple signaling pathways in different cancer types
We demonstrated that the phosphorothioate-modified ‘‘10–23’’ DNAzymes targeted at the latent membrane protein 1 (LMP1) mRNA could significantly down-regulate the expression of LMP1 in a nasopharyngeal carcinoma cell (NPC) and affected the down-stream pathways activated by LMP1, including the nuclear factor kappa B (NF-kB) pathway [18,19]
We hypothesize that ATM expression can be regulated by LMP1 through the NF-kB pathways, which resulted in the change of radiosensitivity in NPCs
Summary
Radio-resistance has been one of the impediments in clinical settings for effective cancer therapy, which is thought to be associated with multiple signaling pathways in different cancer types. ATM (ataxia telangiectasia mutated) is a nuclear 350-kDa protein kinase with a carboxylterminal phosphatidylinositol 3kinase-like kinase domain [1]. It functions as a member of a coordinated system that detects DNA breaks; arrests the cells temporarily at G1, S, or G2 checkpoints; and activates DNA repair [2]. 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
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