Abstract
Epidemiological studies indicate that adequate dietary folate is protective against colon cancer, although mechanisms remain largely elusive. We investigated the effects of genetic disruptions of folate transport and metabolism and of dietary folate deficiency in a mouse model of colon cancer, the Apc min/+ mouse. Apc min/+ mice with heterozygous knockout of the gene for reduced folate carrier 1 ( Rfc1 +/−) developed significantly fewer adenomas compared to Rfc1 +/+ Apc min/+ mice [30.3±4.6 vs. 60.4±9.4 on a control diet (CD) and 42.6±4.4 vs. 55.8±7.6 on a folate-deficient diet, respectively]. Rfc1 +/− Apc min/+ mice also carried a lower tumor load, an indicator of tumor size as well as of tumor number. In contrast, there were no differences in adenoma formation between Apc min/+ mice carrying a knockout allele for methionine synthase ( Mtr +/−), an enzyme that catalyzes folate-dependent homocysteine remethylation, and Mtr +/+ Apc min/+ mice. However, in both Mtr groups of mice, dietary folate deficiency significantly increased adenoma number (from 32.3±3.8 on a CD to 48.1±4.2 on a folate-deficient diet), increased plasma homocysteine, decreased global DNA methylation in preneoplastic intestines and increased apoptosis in tissues. There were no genotype-associated differences in these parameters in the Rfc1 group, suggesting that the protection conferred by Rfc1 deficiency is carried out through a different mechanism. In conclusion, genetic and nutritional disturbances in folate metabolism can have distinct influences on tumorigenesis in Apc min/+ mice; altered levels of homocysteine, global DNA methylation and apoptosis may contribute mechanistically to dietary influence.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.