Effect of DNAzymes targeting Akt1 on cell proliferation and apoptosis in nasopharyngeal carcinoma.
The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is important in nasopharyngeal carcinoma (NPC) pathogenesis. Activated PI3K and its downstream target Akt are concernful signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis and oncogenesis. The protein kinase Akt1, one of the Akt family members, is involved in several signaling pathways for tumor development and progression, suggesting that Akt1 might be an interesting target for a molecular tumor therapy. DNAzyme is a single-stranded DNA catalyst that can be engineered to bind to their complementary sequence in the target mRNA and cleave the mRNA. In this study, based on the analysis of sequences, thermodynamics and site distribution within the Akt1 gene, five DNAzymes were designed. We found that the DNAzyme, namely Dz2, strongly inhibited Akt1 mRNA and protein expression in the NPC cell line CNE1-LMP1. It was showed that the inhibition of cell proliferation, stimulation of apoptosis and inhibition of xenograft growth in nude mice can also exerted by Dz2. Besides, the apoptosis was shown to be associated with the suppression of the Bcl-2 and increased expression of Bax. Thus, DNAzyme targeting Akt1, Dz2, can inhibit multiple key tumorigenic processes in vitro and in vivo and may serve as a useful anti-cancer agent in NPC.
Yang
Lifang
L
Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Xiao
Lanbo
L
Ma
Xiaoqian
X
Tang
Min
M
Weng
Xinxiang
X
Chen
Xue
X
Sun
Lunquan
L
Cao
Ya
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D021881:DNA, Catalytic / Q000494:pharmacology*; D015536:Down-Regulation; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D051023:BH3 Interacting Domain Death Agonist Protein; C107489:BIRC5 protein, human; D021881:DNA, Catalytic; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D000077022:Survivin; D051028:bcl-2-Associated X Protein; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt