Resorting the function of the colorectal cancer gatekeeper adenomatous polyposis coli.
Adenomatous Polyposis Coli
/ diagnostic imaging
Adenomatous Polyposis Coli Protein
/ genetics
Administration, Oral
Adolescent
Adult
Aged
Child
Codon, Nonsense
Codon, Terminator
/ genetics
Colonoscopy
Erythromycin
/ administration & dosage
Feasibility Studies
Female
Follow-Up Studies
Humans
Male
Middle Aged
Transcription, Genetic
/ drug effects
Treatment Outcome
adenomatous polyposis coli
colorectal cancer
familial adenomatous polyposis
nonsense mutation read-through
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 02 2020
15 02 2020
Historique:
received:
18
05
2019
accepted:
01
07
2019
pubmed:
10
7
2019
medline:
3
4
2020
entrez:
9
7
2019
Statut:
ppublish
Résumé
As a large number of cancers are caused by nonsense mutations in key genes, read-through of these mutations to restore full-length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read-through as a potential chemo-preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read-through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor-suppressing activity. Together, our findings show that induced read-through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.
Substances chimiques
APC protein, human
0
Adenomatous Polyposis Coli Protein
0
Codon, Nonsense
0
Codon, Terminator
0
Erythromycin
63937KV33D
Types de publication
Clinical Trial, Phase IV
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1064-1074Informations de copyright
© 2019 UICC.
Références
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology 2010;138:2044-58.
Heinen CD. Genotype to phenotype: analyzing the effects of inherited mutations in colorectal cancer families. Mutat Res 2010;693:32-45.
Lynch PM, Burke CA, Phillips R, et al. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut 2016;65:286-95.
Arber N, Levin B. Chemoprevention of colorectal neoplasia: the potential for personalized medicine. Gastroenterology 2008;134:1224-37.
Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873-84.
Ricciardiello L, Ahnen DJ, Lynch PM. Chemoprevention of hereditary colon cancers: time for new strategies. Nat Rev Gastroenterol Hepatol 2016;13:352-61.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330-7.
Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235-7.
Miyoshi Y, Nagase H, Ando H, et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1992;1:229-33.
Albuquerque C, Breukel C, van der Luijt R, et al. The 'just-right' signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 2002;11:1549-60.
Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol 2012;4:a008052.
Wang D, Liang S, Zhang Z, et al. A novel pathogenic splice acceptor site germline mutation in intron 14 of the APC gene in a Chinese family with familial adenomatous polyposis. Oncotarget 2017;8:21327-35.
Floquet C, Deforges J, Rousset JP, et al. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res 2011;39:3350-62.
Bidou L, Allamand V, Rousset JP, et al. Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med 2012;18:679-88.
Zingman LV, Park S, Olson TM, et al. Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy. Clin Pharmacol Ther 2007;81:99-103.
Kohler EM, Derungs A, Daum G, et al. Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours. Hum Mol Genet 2008;17:1978-87.
Burke JF, Mogg AE. Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Res 1985;13:6265-72.
Lee HL, Dougherty JP. Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther 2012;136:227-66.
Laurent-Puig P, Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 1998;26:269-70.
Zilberberg A, Lahav L, Rosin-Arbesfeld R. Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut 2010;59:496-507.
Caspi M, Firsow A, Rajkumar R, et al. A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents. J Mol Med (Berl) 2016;94:469-82.
Mason JW. Antimicrobials and QT prolongation. J Antimicrob Chemother 2017;72:1272-4.
Niedrig D, Maechler S, Hoppe L, et al. Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation. Eur J Clin Pharmacol 2016;72:859-67.
Schneikert J, Behrens J. The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 2007;56:417-25.
Walton SJ, Frayling IM, Clark SK, et al. Gastric tumours in FAP. Fam Cancer 2017;16:363-9.
Dow LE, O'Rourke KP, Simon J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 2015;161:1539-52.
Faux MC, Ross JL, Meeker C, et al. Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion. J Cell Sci 2004;117:427-39.
Keeling KM, Xue X, Gunn G, et al. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet 2014;15:371-94.
Zhang M, Heldin A, Palomar-Siles M, et al. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Front Oncol 2017;7:323.
Baradaran-Heravi A, Balgi AD, Zimmerman C, et al. Novel small molecules potentiate premature termination codon readthrough by aminoglycosides. Nucleic Acids Res 2016;44:6583-98.
Bidou L, Bugaud O, Belakhov V, et al. Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells. RNA Biol 2017;14:378-88.
Hamoya T, Miyamoto S, Tomono S, et al. Chemopreventive effects of a low-side-effect antibiotic drug, erythromycin, on mouse intestinal tumors. J Clin Biochem Nutr 2017;60:199-207.
Yamamoto M, Kondo A, Tamura M, et al. Long-term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 1990;28:1305-13.
Hankey W, Frankel WL, Groden J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting. Cancer Metastasis Rev 2018;37:159-72.
Castellsague E, Gonzalez S, Guino E, et al. Allele-specific expression of APC in adenomatous polyposis families. Gastroenterology 2010;139:439-47.e1.
Lindeboom RG, Supek F, Lehner B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet 2016;48:1112-8.
Noensie EN, Dietz HC. A strategy for disease gene identification through nonsense-mediated mRNA decay inhibition. Nat Biotechnol 2001;19:434-9.
Zhao Y, Lin J, Xu B, et al. MicroRNA-mediated repression of nonsense mRNAs. Elife 2014;3:e03032.
Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J 2012;40:485-94.
Umeki S. Anti-inflammatory action of erythromycin. Its inhibitory effect on neutrophil NADPH oxidase activity. Chest 1993;104:1191-3.
Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun 2000;267:124-8.
DiDonato JA, Mercurio F, Karin M. NF-kappaB and the link between inflammation and cancer. Immunol Rev 2012;246:379-400.
Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991;1072:129-57.