Downregulation of Sirt1 by antisense oligonucleotides induces apoptosis and enhances radiation sensitization in A549 lung cancer cells

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 58; no. 1; pp. 21 - 29
• Main Authors: Sun, Yuning, Sun, Daochun, Li, Fang, Tian, Linlin, Li, Chunrong, Li, Lu, Lin, Ruxian, Wang, Shengqi
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.10.2007; Elsevier Science
• Subjects: Acetylation; Antisense oligonucleotides; Apoptosis; Apoptosis - genetics; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - radiation effects; Cell Survival - genetics; Cell Survival - radiation effects; Down-Regulation; G1 Phase - genetics; G1 Phase - radiation effects; Gene Expression Regulation, Neoplastic; Genetic Therapy; Hematology, Oncology and Palliative Medicine; Humans; Ionizing radiation; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Medical sciences; Oligonucleotides, Antisense; Pneumology; Pulmonary/Respiratory; Sirt1; Sirtuin 1; Sirtuins - antagonists & inhibitors; Sirtuins - genetics; Sirtuins - metabolism; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tumors of the respiratory system and mediastinum; Antisense oligonucleotides; Ionizing radiation; Sirt1; Apoptosis; Lung disease; Respiratory disease; Lung cancer; Malignant tumor; Antisense oligonucleotide; Cancerology; Bronchus disease; Sensitization; Tumor cell; Pneumology
• ISSN: 0169-5002; 1872-8332
• DOI: 10.1016/j.lungcan.2007.05.013

Summary 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.