Abstract 899: Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism

Abstract

Abstract The role of folate one-carbon metabolism in colorectal cancer development is incompletely understood, and nutritional intervention studies have produced conflicting results. We previously demonstrated that a diet deficient in the methyl donors folic acid, methionine, choline and vitamin B12, and supplemented with homocysteine, reduces intestinal tumor incidence by greater than 95% in ApcMin/+ mice. Here we extend these findings to a second mouse tumor model, ApcÄ14, and further show that the cancer protection afforded by even short-term dietary methyl donor deficiency (MDD) is long-lasting. Eleven weeks of MDD followed by methyl donor repletion was sufficient to maintain tumor suppression for at least 7 additional weeks (22.2 ± 3.5 vs 70.2 ± 4.6 intestinal tumors; p < 0.001). Sustained tumor protection was associated with altered intestinal crypt homeostasis. MDD increased the proportion of intestinal epithelial cells undergoing apoptosis in normal crypts and in tumors (4.9- and 3.2-fold, respectively), while reducing cell proliferation (Ki-67) and mitosis (PHH3). In addition, metabolomic profiling and metabolite set enrichment analysis (MSEA) revealed that tumor protection is associated with persistent alterations to metabolic pathways related to cellular proliferation, including glutamine metabolism, biogenic amine synthesis, nucleotide salvage and glutathione synthesis. Taken together, these results indicate that even a temporary dietary methyl donor restriction in cancer-prone mice can induce persistent changes to the intestinal epithelium that provide long-lasting protection in adult mice. Citation Format: Matthew P. Hanley, Daniel W. Rosenberg. Cancer protection associated with dietary methyl donor deficiency is characterized by persistent changes to epithelial proliferation and metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 899.