Mthfd1 is a modifier of chemically induced intestinal carcinogenesis.

Abstract

The causal metabolic pathways underlying associations between folate and risk for colorectal cancer (CRC) have yet to be established. Folate-mediated one-carbon metabolism is required for the de novo synthesis of purines, thymidylate and methionine. Methionine is converted to S-adenosylmethionine (AdoMet), the major one-carbon donor for cellular methylation reactions. Impairments in folate metabolism can modify DNA synthesis, genomic stability and gene expression, characteristics associated with tumorigenesis. The Mthfd1 gene product, C1-tetrahydrofolate synthase, is a trifunctional enzyme that generates one-carbon substituted tetrahydrofolate cofactors for one-carbon metabolism. In this study, we use Mthfd1(gt/+) mice, which demonstrate a 50% reduction in C1-tetrahydrofolate synthase, to determine its influence on tumor development in two mouse models of intestinal cancer, crosses between Mthfd1(gt/+) and Apc(min)(/+) mice and azoxymethane (AOM)-induced colon cancer in Mthfd1(gt/+) mice. Mthfd1 hemizygosity did not affect colon tumor incidence, number or load in Apc(min/+) mice. However, Mthfd1 deficiency increased tumor incidence 2.5-fold, tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. DNA uracil content in the colon was lower in Mthfd1(gt/+) mice, indicating that thymidylate biosynthesis capacity does not play a significant role in AOM-induced colon tumorigenesis. Mthfd1 deficiency-modified cellular methylation potential, as indicated by the AdoMet: S-adenosylhomocysteine ratio and gene expression profiles, suggesting that changes in the transcriptome and/or decreased de novo purine biosynthesis and associated mutability cause cellular transformation in the AOM CRC model. This study emphasizes the impact and complexity of gene-nutrient interactions with respect to the relationships among folate metabolism and colon cancer initiation and progression.

• Authors: Amanda J MacFarlane, Cheryll A Perry, Michael F McEntee, David M Lin, Patrick J Stover
• Journal: Carcinogenesis (Carcinogenesis) Vol. 32 Issue 3 Pg. 427-33 (Mar 2011) ISSN: 1460-2180 [Electronic] England
• PMID: 21156972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Carcinogens
• DNA, Neoplasm
• Mthfd1 protein, mouse
• Multienzyme Complexes
• Multifunctional Enzymes
• RNA, Messenger
• Uracil
• formyl-methenyl-methylenetetrahydrofolate synthetase
• S-Adenosylmethionine
• S-Adenosylhomocysteine
• Methylenetetrahydrofolate Dehydrogenase (NADP)
• Aminohydrolases
• Methenyltetrahydrofolate Cyclohydrolase
• Formate-Tetrahydrofolate Ligase
• Azoxymethane

Topics

• Aminohydrolases (genetics, physiology)
• Animals
• Apoptosis
• Azoxymethane (toxicity)
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Carcinogens (toxicity)
• Cell Proliferation
• Colonic Neoplasms (chemically induced, genetics, metabolism, pathology)
• DNA, Neoplasm (metabolism)
• Disease Models, Animal
• Female
• Formate-Tetrahydrofolate Ligase (genetics, physiology)
• Gene Expression Profiling
• Immunoenzyme Techniques
• Male
• Methenyltetrahydrofolate Cyclohydrolase (genetics, physiology)
• Methylenetetrahydrofolate Dehydrogenase (NADP) (genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Multienzyme Complexes (genetics, physiology)
• Multifunctional Enzymes (genetics, physiology)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• S-Adenosylhomocysteine (metabolism)
• S-Adenosylmethionine (metabolism)
• Uracil (metabolism)