title: Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides.
abstract: Mutation-based treatments are a new development in genetic medicine, in which the nature of the mutation dictates the therapeutic strategy. Interest has recently focused on diseases caused by premature termination codons (PTCs). Drugs inducing the readthrough of these PTCs restore the production of a full-length protein. In this study, we explored the possibility of using aminoglycoside antibiotics to induce the production of a full-length functional p53 protein from a gene carrying a PTC. We identified a human cancer cell line containing a PTC, for which high levels of readthrough were obtained in the presence of aminoglycosides. Using these cells, we demonstrated that aminoglycoside treatment stabilized the mutant mRNA, which would otherwise have been degraded by non-sense-mediated decay, resulting in the production of a functional full-length p53 protein. Finally, we showed that aminoglycoside treatment decreased the viability of cancer cells specifically in the presence of nonsense-mutated p53 gene. These results open possibilities of developing promising treatments of cancers linked with non-sense mutations in tumor suppressor genes. They show that molecules designed to induce stop-codon readthrough can be used to inhibit tumor growth and offer a rational basis for developing new personalized strategies that could diversify the existing arsenal of cancer therapies.
authors.affiliation: Univ Paris-Sud, Institut de Génétique et Microbiologie, UMR8621, Orsay F-91405.
authors.forename: Célia
authors.initials: C
authors.lastname: Floquet
authors.forename: Jules
authors.initials: J
authors.lastname: Deforges
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rousset
authors.forename: Laure
authors.initials: L
authors.lastname: Bidou
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D016158:Genes, p53; D005839:Gentamicins / Q000494:pharmacology; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D005839:Gentamicins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000583:Amikacin