readthrough of premature termination codons in the adenomatous polyposis coli gene restores its biological activity in human cancer cellsreadthrough过早终止密码子的腺瘤息肉病杆菌基因在人类癌症细胞恢复其生物活性.pdfVIP

Readthrough of Premature Termination Codons in the Adenomatous Polyposis Coli Gene Restores Its Biological Activity in Human Cancer Cells ´ 1,2 1,2 1,3 Celia Floquet , Jean-Pierre Rousset , Laure Bidou * ´ ´ ´ ´ 1 Institut de Genetique et Microbiologie, CNRS, UMR 8621, Orsay, France, 2 Universite Paris-Sud, Orsay, France, 3 Universite Pierre et Marie Curie, Paris, France Abstract The APC tumor suppressor gene is frequently mutated in human colorectal cancer, with nonsense mutations accounting for 30% of all mutations in this gene. Reintroduction of the WT APC gene into cancer cells generally reduces tumorigenicity or induces apoptosis. In this study, we explored the possibility of using drugs to induce premature termination codon (PTC) readthrough (aminoglycosides, negamycin), as a means of reactivating endogenous APC. By quantifying the readthrough of 11 nonsense mutations in APC, we were able to identify those giving the highest levels of readthrough after treatment. For these mutations, we demonstrated that aminoglycoside or negamycin treatment led to a recovery of the biological activity of APC in cancer cell lines, and showed that the level of APC activity was proportional to the level of induced readthrough. These findings show that treatment with readthrough inducers should be considered as a potential strategy for treating cancers caused by nonsense mutations APC gene. They also provide a rational basis for identifying mutations responsive to readthrough inducers. Citation: Floquet C, Rousset J-P, Bidou L (2011) Readthrough of Premature Termination Codons in the Adenomatous Polyposis Coli Gene Restores Its Biological Activity in Human Cancer Cells. PLoS ONE 6(