Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells
Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells
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DOI：
10.1074/jbc.m802942200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Waalkes, Michael P.
中科院分区：
文献类型：
--
作者：
Coppin, Jean-Francois;Qu, Wei;Waalkes, Michael P.
长期低水平砷暴露后，正常的人前列腺上皮细胞系RWPE-1获得一个恶性表型与DNA低甲基化，指示破坏甲基代谢，并显示砷适应谷胱甘肽过量生产和增强砷流出。因此，甲基和谷胱甘肽代谢之间的相互作用，在这种渐进的砷适应进行了研究。砷处理的细胞表现出LC 50的时间依赖性增加和同型半胱氨酸（Hcy）水平显着增加。甲硫氨酸腺苷转移酶2A（将甲硫氨酸转化为SAM）表达减少，负调节因子甲硫氨酸腺苷转移酶B表达增加，S-腺苷甲硫氨酸（SAM）水平显著抑制，表明Hcy转化为SAM减少。与Hcy过量产生一致，S-腺苷高半胱氨酸水解酶（将S-腺苷高半胱氨酸转化为Hcy）的活性和表达均增加。胱硫醚β-合成酶（转硫途径中的关键基因）和各种谷胱甘肽生产基因的表达增加，导致谷胱甘肽增加5倍。砷流出增加沿着与ATP结合盒蛋白C1的表达，其流出砷作为谷胱甘肽共轭物。在早期砷暴露过程中观察到基因组DNA低甲基化的证据，表明甲基代谢的破坏具有与肿瘤发生相关的潜在影响。因此，细胞砷适应是一个动态的，渐进的过程，涉及减少SAM再循环和同时积累的同型半胱氨酸，这是通过转硫增加谷胱甘肽和增强砷流出，但也可能影响致癌过程。
After protracted low level arsenic exposure, the normal human prostate epithelial cell line RWPE-1 acquires a malignant phenotype with DNA hypomethylation, indicative of disrupted methyl metabolism, and shows arsenic adaptation involving glutathione overproduction and enhanced arsenic efflux. Thus, the interplay between methyl and glutathione metabolism during this progressive arsenic adaptation was studied. Arsenic-treated cells showed a time-dependent increase in LC50 and a marked increase in homocysteine (Hcy) levels. A marked suppression of S-adenosylmethionine (SAM) levels occurred with decreased methionine adenosyltransferase 2A (converts methionine to SAM) expression and increased negative regulator methionine adenosyltransferase B, suggesting reduced conversion of Hcy to SAM. Consistent with Hcy overproduction, activity and expression of S-adenosylhomocysteine hydrolase (converts S-adenosylhomocysteine to Hcy) were both increased. Expression of cystathionine beta-synthase, a key gene in the transsulfuration pathway, and various glutathione production genes were increased, resulting in a 5-fold increase in glutathione. Arsenic efflux increased along with expression of ATP-binding cassette protein C1, which effluxes arsenic as a glutathione conjugate. Evidence of genomic DNA hypomethylation was observed during early arsenic exposure, indicating that the disruption in methyl metabolism had a potential impact related to oncogenesis. Thus, cellular arsenic adaptation is a dynamic, progressive process that involves decreased SAM recycling and concurrent accumulation of Hcy, which is channeled via transsulfuration to increase glutathione and enhance arsenic efflux but may also impact the carcinogenic process.