title: Therapeutic potential of antisense oligodeoxynucleotides in downregulating p53 oncogenic mutations in cancers.
abstract: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Kian Ghee
authors.initials: KG
authors.lastname: Tay
authors.forename: Shaw Cheng
authors.initials: SC
authors.lastname: Liu
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D020125:Mutation, Missense; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D016159:Tumor Suppressor Protein p53