Abstract
Purpose of work
Mutation of the p53 gene is the most common genetic alteration in human cancers. Our study proposes to rationally design a p53 antisense oligonucleotide (ASO) repository, which contains a series of ASOs containing single nucleotide differences to discriminate between each mutant and wild type (WT) p53.
The Sfold software was used to predict target-accessibility and we designed an initial series of antisense oligonucleotides (ASO) that target the p53 mutants A161T, R175H and R249S. Western-blot analysis indicated that ASOs strongly inhibited the expression of p53 mutants in a panel of human tumor cell lines (SNU-449, SK-BR-3 and PLC/PRF/5) while having little effect on the expression of WT p53 (HepG2 cells). In three cancer lines harboring each of the p53 mutations, mutant-specific ASO treatment led to a dose-dependent inhibition of cell growth, cell viability, colony formation and invasion, and expression of mutant p53-dependent survival proteins. Our preliminary results indicate that a single nucleotide difference in ASOs can discriminate between mutant and WT p53. These observations support the hypothesis that a p53 ASO repository can be a potentially valuable tool to knock down oncogenic mutant p53 and warrant the testing of a p53 ASO repository in in vivo settings.
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Acknowledgments
This study was supported in part by the Singapore Cancer Syndicate Grant (TN0031, AN0038), and the Terry Fox Run Cancer Research Grant 2004 (Chien-Shing Chen). Wee Joo Chng was supported in part by the National Medical Research Council of Singapore Clinician Scientist Award.
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Xie, Z., Chng, W.J., Tay, K.G. et al. Therapeutic potential of antisense oligodeoxynucleotides in downregulating p53 oncogenic mutations in cancers. Biotechnol Lett 33, 221–228 (2011). https://doi.org/10.1007/s10529-010-0423-5
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DOI: https://doi.org/10.1007/s10529-010-0423-5