Folates are water-soluble B vitamins, which maintain DNA stability by regulating nucleotide synthesis and DNA methylation. Folates influence CRC risk and their ability to prevent or promote carcinogenesis may be dependent on several variables here investigated. No in vitro study has yet modelled the physiological folate status that human colon cells are exposed to in vivo. This study evaluates the ability of different forms and concentrations of folate to maintain DNA stability and normal cell function in folate-sufficient and stable human colonocytes and to modify DNA instability and the acquisition of abnormal characteristics in folate-deficient and genomically-unstable colonocytes. Non-malignant human NCM460 colonocytes cultured at physiologically-relevant concentrations of 5-methyl-THF or FA, representing the average deficient (2.5 ng/mL), sufficient (10 ng/mL) or highest post-supplementation (100 ng/mL) folate levels found in human plasma were used in this study as a model of colon-folate interaction. This work established that FA is taken up and/or retained to a lesser extent than 5-methylTHF and is less efficient at maintaining DNA stability and normal cellular characteristics in folate-sufficient and genomically-stable colonocytes at baseline, particularly at deficient and sufficient concentrations in the medium to longer term (14-21 days). During repletion of folate-deficient and genomically-unstable cells, sufficient concentrations of FA do not increase intracellular folate status and worsen the unstable phenotype, by perpetuating DNA instability and enabling the acquisition of a more pro-malignant protein expression. On the contrary, employing 5-methyl-THF sufficiency for repletion positively modifies the abnormal protein profile and morphological features of folate-deficient cells, mitigating potential progression to malignant transformation. When high post-supplementation concentrations are employed, both folate forms increase intracellular folate status, but drive a more promalignant and stress-induced proteome profile and, in the case of 5-methyl-THF, promote abnormal cell morphologies. In conclusion, the folate type, concentration employed, baseline folate status and timing of exposure to folate supplementation are important variables that should be taken into account by future studies evaluating the potential impact of mandatory FA fortification on CRC.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:715469 |
| Date | January 2017 |
| Creators | Nadal Catala, Gema |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=231796 |
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