title: Azoxymethane-induced colon carcinogenesis in mice occurs independently of de novo thymidylate synthesis capacity.
abstract: 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.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors: Amanda J
authors: AJ
authors: MacFarlane
authors: Michael F
authors: MF
authors: McEntee
authors: Patrick J
authors: PJ
authors: Stover
mesh_terms: D000818:Animals; D001397:Azoxymethane; D063646:Carcinogenesis / Q000378:metabolism*; D002796:Choline Deficiency / Q000503:physiopathology; D003106:Colon / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003433:Crosses, Genetic; D004247:DNA / Q000378:metabolism*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000009:adverse effects / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000503:physiopathology; D012696:Glycine Hydroxymethyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D013938:Thymidine Monophosphate / Q000378:metabolism*; D047368:Tumor Burden; D014498:Uracil / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; C077112:Lox protein, mouse; D013938:Thymidine Monophosphate; D014498:Uracil; D004247:DNA; D005492:Folic Acid; D008249:Protein-Lysine 6-Oxidase; D012696:Glycine Hydroxymethyltransferase; C559685:Shmt1 protein, mouse; D001397:Azoxymethane