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Triggering apoptosis by oroxylin A through caspase-8 activation and p62/SQSTM1 proteolysis.
Redox Biology ( IF 10.7 ) Pub Date : 2019-11-28 , DOI: 10.1016/j.redox.2019.101392
Yue Zhao 1 , Qin Zhu 1 , Xiumin Bu 1 , Yihui Zhou 1 , Dongsheng Bai 1 , Qinglong Guo 1 , Yuan Gao 1 , Na Lu 1
Affiliation  

Emerging evidence suggests that oroxylin A exhibits antitumor effects by inducing cell apoptosis. However, the involved molecular mechanisms have not been elucidated. Here we report that the apoptosis induced by oroxylin A was dependent on p62-mediated activation of caspase-8 in hepatocellular carcinoma cells. Furthermore, oroxylin A also caused p62/SQSTM1 proteolysis at Asp329 by activating caspase-8. Further studies confirm that mutation in p62 (D329H and D329G) was resistant to oroxylin A-mediated p62 cleavage and apoptosis. Due to the absence of the KIR domain that interacts with Keap1, the cleaved p62 reduced the stability of Nrf2, thereby causing oxidative stress and increasing ROS levels. In vivo, p62 similarly contributed to oroxylin A-exerted antitumor effect in xenograft model inoculated SMMC-7721 tumor. In conclusion, our findings indicated that oroxylin A triggered apoptosis through caspase-8 activation and p62/SQSTM1 proteolysis.



中文翻译:

通过半胱天冬酶A激活caspase-8激活和p62 / SQSTM1蛋白水解来触发细胞凋亡。

新兴证据表明,木犀草素A通过诱导细胞凋亡显示出抗肿瘤作用。但是,尚未阐明所涉及的分子机制。在这里我们报告说,由氧化羟色胺A诱导的凋亡依赖于肝细胞癌细胞中p62介导的caspase-8的活化。此外,通过激活半胱天冬酶8,木犀草素A还引起Asp329的p62 / SQSTM1蛋白水解。进一步的研究证实,p62中的突变(D329H和D329G)对羟丙甲毒素A介导的p62裂解和凋亡具有抗性。由于缺少与Keap1相互作用的KIR域,切割的p62降低了Nrf2的稳定性,从而导致氧化应激并增加ROS水平。体内在异种移植模型接种的SMMC-7721肿瘤中,p62,p62相似地促进了木糖精蛋白表达的抗肿瘤作用。总而言之,我们的发现表明,木犀草素A通过caspase-8激活和p62 / SQSTM1蛋白水解触发了细胞凋亡。

更新日期:2019-11-28
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