Dietary uridine decreases tumorigenesis in the ApcMin/+ model of intestinal cancer

Abstract

Background: Dietary deoxyuridine and uridine have been shown to have opposing effects on neural tube defect (NTD) incidence in the serine hydroxymethyltransferase 1 (Shmt1+/-) mouse model of folate-responsive NTDs, which are mediated by changes in de novo thymidylate biosynthesis. Alterations in folate-mediated one-carbon metabolism that protect against NTDs increased cancer risk in some studies. Objective: This study examined the effects of the dietary pyrimidine nucleosides uridine, thymidine, or deoxyuridine on intestinal tumorigenesis in the ApcMin/+ mouse model [a mouse model lacking one copy of the adenomatosis polypsis coli (APC) gene] of spontaneous intestinal tumor formation. This study also evaluated the effects of uridine and deoxyuridine in culture medium on antifolate efficacy in Caco-2 and HeLa cell lines. Methods: ApcMin/+ male mice (n = 10-14/group) were fed folate-deficient diets containing uridine, thymidine, or deoxyuridine from weaning until 17 wk of age. Total intestinal tumors were analyzed and biomarkers of folate status and metabolism were measured, including plasma folate concentrations, colon uracil content, and SHMT1 concentrations. Results: ApcMin/+ mice fed dietary uridine showed a 50% reduction in total intestinal tumors, but neither dietary deoxyuridine nor thymidine affected tumorigenesis. Dietary nucleoside supplementation also increased plasma folate concentrations in ApcMin/+ mice, as has been observed in the Shmt1+/- mouse model. Neither uridine nor deoxyuridine in culture media affected antifolate efficacy in either HeLa or Caco-2 cell lines. Conclusions: Dietary uridine, which is teratogenic in mice, decreases intestinal tumor formation in the ApcMin/+ mouse model. Dietary uridine mimics the effect of the common methylene tetrahydrofolate reductase (MTHFR) C677T variant in protecting against colorectal cancer, while contributing to the risk of NTDs.