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 ApcMin/+ mouse model, these compounds ameliorated the tumorigenic clinical symptoms caused by nonsense mutations in the APC gene.
- Adenomatous polyposis coli (APC)
- colorectal cancer (CRC)
- nonsense mutations
- aminoglycoside and macrolide antibiotics
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Funding Israeli Academy of Sciences, The Association for International Cancer Research (AICR) from the Public Committee for Allocation of Estate Funds, Ministry of Justice, Israel (grant no. 0113406), Israel Cancer Research Fund (ICRF), Israel Cancer Research fund, NIH grant R03CA113252 and the Recanati Foundation.
Competing interests None.
Ethics approval The study was performed according the guidelines of the Institutional Animal Care Committee of Tel Aviv University.
Provenance and peer review Not commissioned; externally peer reviewed.