Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons

Abstract

Adenomatous polyposis coli (APC) is a multifunctional tumour suppressor protein that negatively regulates the Wnt signalling pathway. The APC gene is ubiquitously expressed in tissues and organs, including the large intestine and central nervous system. The majority of patients with sporadic and hereditary colorectal cancer have mutations in the gene encoding APC. Approximately 30% of these mutations are single nucleotide changes that result in premature stop codons (nonsense mutations). A potential therapeutic approach for treatment of this subset of patients is the use of aminoglycosides and macrolides that induce nonsense mutation read-through and restore levels of full-length protein. We have used reporter plasmids and colorectal cancer cell lines to demonstrate that several aminoglycosides and tylosin, a member of the macrolide family, induced read-through of nonsense mutations in the APC gene. In xenograft experiments and in the Apc(Min/+) mouse model, these compounds ameliorated the tumorigenic clinical symptoms caused by nonsense mutations in the APC gene.

Cancer syndromes and therapy by stop-codon readthrough

“…Aminoglycosides and the macrolide antibiotic tylosin induced readthrough of mutant APC and restored its function in human CRC cell lines and mouse models [67]. Nonsense mutations in TP53 were suppressed by aminoglycosides [68], recovering functional full-length protein in several cancer cell lines [69].…”

Sense from nonsense: therapies for premature stop codon diseases

“…Finally, tylosin, a member of the macrolide family binding to the E site of the large ribosomal subunit [65], was shown to suppress nonsense mutations in the APC gene in a study of colorectal cancer, thereby improving tumorigenic symptoms in the Apc Min/+ mouse model (carrying a Glu850X mutation) [66].…”

Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

“…5,6 Further experiments with gentamicin, both in mouse models of CF 7 and DMD 8 and in clinical trials with patients of these two diseases 9,10 carrying nonsense mutations in CFTR and Dystrophin genes, respectively, evidently demonstrated partial production of missing proteins. Other genetic disorders for which the therapeutic potential of aminoglycosides was tested in in vitro systems, cultured cell lines, or animal models including cancer, 11 Rett syndrome, 12 Hurler syndrome, 13 nephrogenic diabetes insipidus, 14 nephropathic cystinosis, 15 retinitis pigmentosa, 16 ataxia-telangiectasia 17 and more.…”