Colorectal cancer (CRC) is the third most common malignancy in the western hemisphere, and 1 of the leading causes of worldwide morbidity and mortality due to cancer. Molecular studies have pinpointed activating mutations of the Wnt signalling pathway as the cause of approximately 90% of all CRCs and somewhat less frequently in cancers at other sites such as breast, liver and prostate. Mutations mimicking Wnt stimulation - generally inactivation mutations in the tumour suppressor gene - adenomatous polyposis coli (APC) results in nuclear accumulation of b-catenin which subsequently complexes with T-cell factor/lymphoid enhancing factor to activate gene transcription. These changes in transcription are thought to be the basis for tumorigenesis. In addition, APC functions in cell-cell contact and its loss in cancer cells seems to decrease cell adhesion. It is thus likely that mutations in APC result in the initiation of colorectal cancer by leading to high levels of Wnt signalling and that by disruption of intracellular adhesion these mutations play a part in cancer progression. Almost all of APC mutations in CRC are nonsense or frameshift mutations that result in a truncated protein. Recently, it has been shown that in addition to their antimicrobial activity aminoglycoside antibiotics can suppress premature stop codons, and lead to the restoration of a full length, functional protein in human genetic diseases that carry disease-causing nonsense mutations. We shall use a reporter plasmid assay, colorectal cancer cell lines and APC loss of function mice to try and induce readthrough of the specific stop mutations in the APC gene by using aminoglycoside antibiotics.
The aim of this application is to investigate the effect of aminoglycosides on the pre-mature stop codons in the APC gene and to induce expression of full length APC in colon cancer cells. This is a novel approach, which, if successful, could open new avenues in the treatment of colorectal cancer and other human genetic diseases. ? ?
| Zilberberg, Alona; Lahav, Lital; Rosin-Arbesfeld, Rina (2010) Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut 59:496-507 |
| Breitman, Maya; Zilberberg, Alona; Caspi, Michal et al. (2008) The armadillo repeat domain of the APC tumor suppressor protein interacts with Striatin family members. Biochim Biophys Acta 1783:1792-802 |
