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ROS-Mediated 15-Hydroxyprostaglandin Dehydrogenase Degradation via Cysteine Oxidation Promotes NAD+-Mediated Epithelial-Mesenchymal Transition
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2018-01-04 , DOI: 10.1016/j.chembiol.2017.12.008
Weixuan Wang , Yadong Hu , Xiaofei Wang , Qingtao Wang , Haiteng Deng

Nicotinamide adenine dinucleotide (NAD) levels decrease with aging as a result of aging-associated CD38 upregulation. Here, we established a cell model with decreased cellular NAD levels by overexpressing CD38 or treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase. We revealed that decreased NAD triggered reactive oxygen species (ROS)-mediated degradation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which drove cells to undergo epithelial-mesenchymal transition (EMT). Moreover, we showed that oxidation of the Cys44 residue to sulfonic acid in 15-PGDH led to its degradation via non-canonical ubiquitination-proteasome and autophagy pathways. Mutation of Cys44 to alanine abolished ROS-induced 15-PGDH degradation. We demonstrated that 15-PGDH silencing promoted EMT, whereas supplementation with NAD precursors increased NAD and 15-PGDH stability, and reversed the EMT process. Taken together, these results suggest that declining NAD levels contribute to age-dependent increases in cancer incidence, and repletion of NAD precursors is beneficial for increasing 15-PGDH expression.

中文翻译:

ROS介导的半胱氨酸氧化降解15-羟基前列腺素脱氢酶可促进NAD +介导的上皮-间充质转化。

烟酰胺腺嘌呤二核苷酸(NAD)水平随衰老而降低,这是衰老相关CD38上调的结果。在这里,我们通过过度表达CD38或用烟酰胺磷酸核糖基转移酶抑制剂FK866处理细胞,建立了细胞NAD水平降低的细胞模型。我们发现减少的NAD触发了活性氧(ROS)介导的15-羟基前列腺素脱氢酶(15-PGDH)降解,驱使细胞进行上皮-间质转化(EMT)。此外,我们表明在15-PGDH中Cys44残基氧化为磺酸会导致其通过非规范泛素化蛋白酶体和自噬途径降解。Cys44突变为丙氨酸消除了ROS诱导的15-PGDH降解。我们证明了15-PGDH沉默促进了EMT,而补充NAD前体可增加NAD和15-PGDH的稳定性,并逆转EMT过程。综上所述,这些结果表明,NAD水平的下降有助于癌症发病率的年龄依赖性增加,并且补充NAD前体有利于增加15-PGDH的表达。
更新日期:2018-03-16
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