Mechanisms in one-carbon nutrients and colon cancer.

PL05-01

Both pre-clinical and clinical studies suggest that diminished folate status increases the risk of colorectal carcinogenesis. Moreover, observations from rodent models of colon cancer as well as an epidemiological association between a common polymorphism in the folate-dependent enzyme, MTHFR, and the occurrence of colorectal neoplasms provide further support for a true mechanistic role for folate in determining the risk of this cancer. Further, the biological plausibility of such a relationship is high given the pivotal role that folate plays in biological methylation and the synthesis and repair of RNA/DNA. However, folate does not perform its important biochemical functions in isolation: these functions are also dependent on the adequate availability of several other 'one-carbon nutrients', including vitamins B2, B6 and B12. We therefore investigated if the mild depletion of folate, alone or in combination with depletion of vitamins B2, B6 and B12 could induce alterations in pro-carcinogenic pathways in the colonic mucosa. Four month old mice were pair-fed diets with different combinations of vitamin depletion. To date, the most remarkable effects noted have been on the Wnt pathway. Genomic DNA hypomethylation and DNA strand breaks within the APC mutation cluster region were significantly induced by mild folate depletion combined with inadequacies of B2, B6, and B12; such effects were not significantly induced by folate depletion alone. Similarly, minor changes in the expression of the APC and b-catenin produced by mild folate depletion were magnified by the combined depletion of the abovementioned B-vitamins. Apoptosis was significantly attenuated only by the combined deficiency state. These findings indicate that a mild depletion of folate that is of insufficient magnitude by itself to induce Wnt pathway alterations may produce such effects when present in conjunction with mild inadequacies of other one-carbon nutrients. These observations underscore the import of multiple states of 'subclinical' depletion that may act in concert with one another and thereby produce pro-carcinogenic effects that would not be produced by a single state of depletion.