DNAzymes targeted to EBV-encoded latent membrane protein-1 induce apoptosis and enhance radiosensitivity in nasopharyngeal carcinoma.
Epstein-Barr virus (EBV) is involved in the carcinogenesis of several types of cancers such as nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma. The latent membrane protein (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. Therefore, genetic manipulation of LMP1 expression may provide a novel strategy for the treatment of the EBV-associated human cancers. Deoxyribozymes (DNAzymes) are catalytic nucleic acids that bind and cleave a target RNA in a highly sequence-specific manner. We have designed several LMP1-specific DNAzymes and tested their effect on cell proliferation and apoptosis in LMP1-positive cells. Here, we show that active DNAzymes down-regulated the expression of the EBV oncoprotein LMP1 and inhibited cellular signal transduction pathways abnormally activated by LMP1. This down-regulation of the LMP1 expression was shown to be associated with a decrease in the level of antiapoptotic Bcl-2 and an increase in Caspase-3 and -9 activities in the nasopharyngeal carcinoma cell line CNE1-LMP1, which constitutively expresses the LMP1. When combined with radiation treatment, the DNAzymes significantly induced apoptosis in CNE1-LMP1 cells, leading to an increased radiosensitivity both in cells and in a xenograft NPC model in mice. The results suggest that LMP1 may represent a molecular target for DNAzymes and provide a basis for the use of the LMP1 DNAzymes as potential radiosensitizers for treatment of the EBV-associated carcinomas.
Lu
Zhong-Xin
ZX
Cancer Research Institute, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, PR China.
Ma
Xiao-Qian
XQ
Yang
Li-Fang
LF
Wang
Zhen-Lian
ZL
Zeng
Liang
L
Li
Zi-Jian
ZJ
Li
Xiao-Nan
XN
Tang
Min
M
Yi
Wei
W
Gong
Jian-Ping
JP
Sun
Lun-Quan
LQ
Cao
Ya
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000821:virology*; D045744:Cell Line, Tumor; D021881:DNA, Catalytic / Q000494:pharmacology*; D005240:Feasibility Studies; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000821:virology*; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014763:Viral Matrix Proteins; D023041:Xenograft Model Antitumor Assays
D021881:DNA, Catalytic; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins