The role of altered folate one-carbon metabolism (FOCM) in the development of colorectal cancer

2018-06-21Background: CRC ranks as the third leading cause of cancer-related death in the industrialized world, responsible for about 50,000 deaths in the United States annually. Aberrant methylation patterns have been implicated in the pathogenesis of CRC and thus make it necessary to probe the folate one-carbon metabolism (FOCM) to explore for any association with CRC risk. ❧ Aims: The main goals of this study were to: 1) Develop a validated metabolomics-based LCMS assay for the FOCM metabolites; 2) Use these metabolomic assays as a platform to explore for blood-based biomarkers in plasma of CRC cases and controls; 3) Explore for differences in the FOCM metabolites and genes for colon cells at different stages in CRC development and 4) Evaluate the cellular effect of folic acid (FA) or 5-methyltetrahydrofolate (5MTHF) supplementation on the FOCM of colon cells at different stages of CRC development.❧ Results: The proportions of the folate metabolites were significantly different in the CRC cases and controls where the accumulation of reduced folate metabolites was observed in the cases. A similar trend was also seen in the transformed cells when compared with the transitional and untransformed colon cells. In addition, there was a significant difference in methionine levels was observed between the two groups. The transformed cells showed upregulation in most of the FOCM genes, except for MTR/MTRR, CBS, and MAT where there were differences based on their microsatellite stability status. The effect of FA or 5MTHF supplementation had opposing effects on the expression of the genes. Although increasing concentrations of FA correlated with increased growth rate, escalating concentration of 5MTHF did not cause a significant change in the cellular growth rate. The group with the combination of 2.3 µM 5MTHF and 9 µM FA was observed to slow down the growth rate observed in the 9 µM FA supplementation group. ❧ Discussion and Conclusions: The accumulation of reduced folate metabolites may be due to the overexpression of folate metabolism genes and a downregulation of MS/MTRR genes. Also, there is an overexpression of proliferation genes as well as their modulation through aberrant methylation that tend to drive cell proliferation. Supplementation with 9 µM FA was associated with significant increase in growth rate in untransformed and transformed colon cell lines, but the addition of 2.3 µM of 5MTHF to the 9 µM FA (to form the Combo) was associated with reduced growth in the transitional and transformed cell lines