Folate deficiency induces cell-specific changes in the steady-state transcript levels of genes involved in folate metabolism and 1-carbon transfer reactions in human colonic epithelial cells
Folate deficiency induces cell-specific changes in the steady-state transcript levels of genes involved in folate metabolism and 1-carbon transfer reactions in human colonic epithelial cells
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DOI：
10.1093/jn/137.3.607
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发表时间：
2007-03-01
影响因子：
4.2
通讯作者：
Kim, Young-In
中科院分区：
文献类型：
--
作者：
Hayashi, Inki;Sohn, Kyoung-Jin;Kim, Young-In
细胞内叶酸稳态对于结肠上皮细胞中DNA合成和生物甲基化反应所必需的1-碳转移反应至关重要。叶酸耗竭导致的1-碳转移反应紊乱使正常结肠上皮细胞易于发生肿瘤转化，同时抑制结肠癌细胞的生长。使用叶酸缺乏的体外模型，我们确定了叶酸缺乏对HCT 116和Caco 2人结肠腺癌细胞中参与细胞内叶酸代谢和1-碳转移反应的基因的稳态转录水平的影响。在HCT 116细胞中，叶酸消耗与基因转录水平的变化有关，这些基因有利于增加叶酸摄取和细胞内叶酸保留，为叶酸依赖性酶提供代谢上更有效的底物，并减少叶酸水解和外排。在HCT 116细胞中，叶酸消耗与基因转录水平的变化有关，这些基因有利于1-碳单位的通量优先穿梭于核苷酸合成途径的甲硫氨酸循环。在Caco 2细胞中，对叶酸耗竭的一些适应性反应不如HCT 116细胞明显，在某些情况下，变化的方向是违反直觉的。在Caco 2细胞中，响应于叶酸消耗的代谢优先级是以生物甲基化反应为代价将可用的叶酸池穿梭到核苷酸生物合成途径。在HCT 116和Caco 2细胞中，叶酸消耗与DNA甲基化的现有模式和程度的保守性相关。
Intracellular folate homeostasis is essential for the 1-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions in colonic epithelial cells. Perturbed 1-carbon transfer reactions resulting from folate depletion predispose normal colonic epithelial cells to neoplastic transformation while inhibiting the growth of colon cancer cells. Using an in vitro model of folate deficiency, we determined the effects of folate deficiency on the steady-state transcript levels of genes involved in intracellular folate metabolism and 1-carbon transfer reactions in HCT116 and Caco2 human colon adenocarcinoma cells. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring increased folate uptake and intracellular folate retention, the provision of metabolically more effective substrates for folate-dependent enzymes, and reduced folate hydrolysis and efflux. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring the preferential shuttling of the flux of 1-carbon units to the methionine cycle over the nucleotide synthesis pathway. In Caco2 cells, some adaptive responses in response to folate depletion were not as apparent as in HCT116 cells, and in some cases, the direction of change was counterintuitive. In Caco2 cells, the metabolic priority in response to folate depletion was to shuttle the available folate pools to the nucleotide biosynthesis pathway at the expense of biological methylation reactions, In both HCT116 and Caco2 cells, folate depletion was associated with the conservation of the existing pattern and extent of DNA methylation.