Downregulation of Sirt1 by antisense oligonucleotides induces apoptosis and enhances radiation sensitization in A549 lung cancer cells.
Sirt1, a conserved nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, has been implicated in modulating transcriptional silencing and cell survival, and seems to play a key role in carcinogenesis through deacetylation of important regulatory proteins. This makes it a potential target in cancer therapy. The purpose of this study was to determine whether inhibition of Sirt1 by using antisense oligonucleotides (ASODN) induces apoptosis and enhances radiation sensitization in A549 lung cancer cells. Initially, transient transfection of A549 lung cancer cells with ASODN against Sirt1 specifically reduced Sirt1 expression in a dose-dependent and sequence-specific manner, at both mRNA and proteins levels. The inhibition of Sirt1 obviously decreased A549 cells survival, induced G1 arrest as well as apoptosis. Furthermore, the inhibition of Sirt1 by ASODN greatly increased radiation-induced antiproliferation effects involving in increasing acetylation of tumour suppressor p53 and Bax expression in A549 lung cancer cells. In summary, our results indicate that downregulation of Sirt1 by ASODN decreases survival and increases radiation-induced antiproliferation effects of human lung cancer cells and suggest that inhibition of Sirt1 by ASODN may be a potential gene therapy approach to the treatment of lung cancer.
Sun
Yuning
Y
Beijing Institute of Radiation Medicine, 27 Taiping Road, Hai-Dian District, Beijing 100850, China.
Sun
Daochun
D
Li
Fang
F
Tian
Linlin
L
Li
Chunrong
C
Li
Lu
L
Lin
Ruxian
R
Wang
Shengqi
S
D000107:Acetylation; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D015536:Down-Regulation; D016193:G1 Phase / Q000235:genetics / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D016376:Oligonucleotides, Antisense; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins