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dc.contributor.authorSheng, YH
dc.contributor.authorGiri, R
dc.contributor.authorDavies, J
dc.contributor.authorSchreiber, V
dc.contributor.authorAlabbas, S
dc.contributor.authorMovva, R
dc.contributor.authorHe, Y
dc.contributor.authorWu, A
dc.contributor.authorHooper, J
dc.contributor.authorMcWhinney, B
dc.contributor.authorOancea, I
dc.contributor.authorKijanka, G
dc.contributor.authorHasnain, S
dc.contributor.authorLucke, AJ
dc.contributor.authorFairlie, DP
dc.contributor.authorMcGuckin, MA
dc.contributor.authorFlorin, TH
dc.contributor.authorBegun, J
dc.date.accessioned2020-11-17T03:23:22Z
dc.date.available2020-11-17T03:23:22Z
dc.date.issued2021-01-01
dc.identifierpii: S2352-345X(20)30088-6
dc.identifier.citationSheng, Y. H., Giri, R., Davies, J., Schreiber, V., Alabbas, S., Movva, R., He, Y., Wu, A., Hooper, J., McWhinney, B., Oancea, I., Kijanka, G., Hasnain, S., Lucke, A. J., Fairlie, D. P., McGuckin, M. A., Florin, T. H. & Begun, J. (2021). A Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 11 (1), pp.33-53. https://doi.org/10.1016/j.jcmgh.2020.05.012.
dc.identifier.issn2352-345X
dc.identifier.urihttp://hdl.handle.net/11343/251487
dc.description.abstractBACKGROUND & AIMS: Chronic bowel inflammation increases the risk of colon cancer; colitis-associated cancer (CAC). Thiopurine treatments are associated with a reduction in dysplasia and CAC in inflammatory bowel disease (IBD). Abnormal Wnt/β-catenin signalling is characteristic of >90% of colorectal cancers. Immunosuppression by thiopurines is via Rac1 GTPase, which also affects Wnt/β-catenin signalling. Autophagy is implicated in colonic tumors, and topical delivery of the thiopurine thioguanine (TG) is known to alleviate colitis and augment autophagy. This study investigated the effects of TG in a murine model of CAC and potential mechanisms. METHODS: Colonic dysplasia was induced by exposure to azoxymethane (AOM) and dextran sodium sulfate (DSS) in wild-type (WT) mice and mice harboring intestinal epithelial cell-specific deletion of autophagy related 7 gene (Atg7ΔIEC). TG or vehicle was administered intrarectally, and the effect on tumor burden and β-catenin activity was assessed. The mechanisms of action of TG were investigated in vitro and in vivo. RESULTS: TG ameliorated DSS colitis in wild-type but not Atg7ΔIEC mice, demonstrating that anti-inflammatory effects of locally delivered TG are autophagy-dependent. However, TG inhibited CAC in both wild-type and Atg7ΔIEC mice. This was associated with decreased β-catenin activation/nuclear translocation demonstrating that TG's inhibition of tumorigenesis occurred independently of anti-inflammatory and pro-autophagic actions. These results were confirmed in cell lines, and the dependency on Rac1 GTPase was demonstrated by siRNA knockdown and overexpression of constitutively active Rac1. CONCLUSIONS: Our findings provide evidence for a new mechanism that could be exploited to improve CAC chemoprophylactic approaches.
dc.languageEnglish
dc.publisherELSEVIER INC
dc.titleA Nucleotide Analog Prevents Colitis-Associated Cancer via Beta-Catenin Independently of Inflammation and Autophagy
dc.typeJournal Article
dc.identifier.doi10.1016/j.jcmgh.2020.05.012
melbourne.affiliation.departmentMedicine Dentistry & Health Sciences
melbourne.source.titleCellular and Molecular Gastroenterology and Hepatology
melbourne.source.volume11
melbourne.source.issue1
melbourne.source.pages33-53
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1451932
melbourne.openaccess.pmchttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593585
melbourne.contributor.authorMcGuckin, Michael
dc.identifier.eissn2352-345X
melbourne.accessrightsOpen Access


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