Hoang Hai Ngo, Bo-Yeung Yu, Jeong-Eun Lee, Hyunwoo Kim, Young-Sam Keum
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引用次数: 0
摘要
癌症基因组测序研究已经确定了KEAP1/NRF2通路中的体细胞突变。为了鉴定新的NRF2小分子抑制剂,我们在a549 - are - gfp -荧光素酶细胞中筛选了包含1330种化学物质的天然化合物文库,并发现水仙环素显著抑制NRF2依赖性荧光素酶活性。水仙碱抑制NRF2和NRF2靶基因的表达,引起明显的氧化应激,并使顺铂介导的A549细胞凋亡增敏。此外,我们观察到WD Repeat Domain 43 (WDR43)是水仙素抑制NRF2的直接靶点,水仙素在体外与重组WDR43结合,沉默WDR43可以减弱水仙素对A549细胞NRF2的抑制作用。最后,我们观察到给药水仙素显著降低了A549异种移植物的生长。综上所述,我们的研究结果表明,水仙素对NRF2的抑制是由WDR43介导的,未来的研究需要进一步阐明WDR43介导水仙素对NRF2抑制的确切机制。
Identification of narciclasine as a novel NRF2 inhibitor.
Cancer genome sequencing studies have identified somatic mutations in the KEAP1/NRF2 pathway. In an effort to identify novel NRF2 small molecule inhibitor(s), we have screened a natural compound library comprising 1330 chemicals in A549-ARE-GFP-luciferase cells and identified that narciclasine significantly inhibits NRF2-dependent luciferase activity. Narciclasine suppressed the expression of NRF2 and NRF2 target genes, caused significant oxidative stress, and sensitized cisplatin-mediated apoptosis in A549 cells. In addition, we have observed that WD Repeat Domain 43 (WDR43) serves as a direct target of narciclasine for the inhibition of NRF2 as narciclasine binds to recombinant WDR43 in vitro and silencing WDR43 attenuated the inhibition of NRF2 by narciclasine in A549 cells. Finally, we observed that administration of narciclasine significantly decreased the growth of A549 xenografts. Together, our results demonstrate that the inhibition of NRF2 by narciclasine is mediated by WDR43 and future studies are necessary to elucidate the exact mechanism of how WDR43 mediates the inhibition of NRF2 by narciclasine.
期刊介绍:
Free Radical Research publishes high-quality research papers, hypotheses and reviews in free radicals and other reactive species in biological, clinical, environmental and other systems; redox signalling; antioxidants, including diet-derived antioxidants and other relevant aspects of human nutrition; and oxidative damage, mechanisms and measurement.