Azoxymethane-Induced Colon Carcinogenesis in Mice Occurs Independently of De Novo Thymidylate Synthesis Capacity
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Folate metabolism affects DNA synthesis, methylation, mutation rates, genomic stability, and gene expression, which are altered in colon cancer. Serine hydroxymethyltransferase 1 (SHMT1) regulates thymidylate (dTMP) biosynthesis and uracil accumulation in DNA, and as such affects genome stability. Previously, we showed that decreased SHMT1 expression in Shmt1 knockout mice (Shmt1(-/+)) or its impaired nuclear localization, as occurs in mice over-expressing an Shmt1 transgene (Shmt1(tg+)), results in elevated uracil incorporation into DNA, which could affect colon cancer risk. We used these 2 models to determine the effect of altered SHMT1 expression and localization, and its interaction with folate insufficiency, on azoxymethane (AOM)-induced colon cancer in mice. Shmt1(-/+) and Shmt1(tg+) mice were weaned to a control or folate-and-choline-deficient (FCD) diet and fed the diet for 28 or 32 wk, respectively. At 6 wk of age, mice were injected weekly for 6 wk with 10 mg/kg AOM (w/v in saline). Colon uracil concentrations in nuclear DNA were elevated 2-7 fold in Shmt1(-/+) and Shmt1(tg+) mice. However, colon tumor incidence and numbers were not dependent on SHMT1 expression in Shmt1(-/+) or Shmt1(-/-) mice. The FCD diet reduced tumor load independent of Shmt1 genotype. In contrast, Shmt1(tg+) mice exhibited a 30% reduction in tumor incidence, a 50% reduction in tumor number, and a 60% reduction in tumor load compared with wild-type mice independent of dietary folate intake. Our data indicate that uracil accumulation in DNA does not predict tumor number in AOM-mediated carcinogenesis. Furthermore, enrichment of SHMT1 in the cytoplasm, as observed in Shmt1(tg+) mice, protects against AOM-mediated carcinogenesis independent of its role in nuclear de novo dTMP biosynthesis.
author list (cited authors)
MacFarlane, A. J., McEntee, M. F., & Stover, P. J.