Promotion of HeLa cells apoptosis by cynaropicrin involving inhibition of thioredoxin reductase and induction of oxidative stress
Promotion of HeLa cells apoptosis by cynaropicrin involving inhibition of thioredoxin reductase and induction of oxidative stress
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Cynaropicrin 促进 HeLa 细胞凋亡涉及抑制硫氧还蛋白还原酶和诱导氧化应激
DOI：
10.1016/j.freeradbiomed.2019.03.014
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发表时间：
2019-05-01
影响因子：
7.4
通讯作者：
Fang, Jianguo
中科院分区：
文献类型：
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作者：
Liu, Tianyu;Zhang, Junmin;Fang, Jianguo
癌症被认为是全球高度致命的疾病之一。这在很大程度上是由于缺乏有效的肿瘤药物，因此迫切需要开发有效的抗癌剂。硫氧还蛋白（Trx）系统对细胞的存活能力至关重要，并且其表达在许多人类肿瘤中上调。近年来，越来越多的证据表明，哺乳动物硫氧还蛋白还原酶（TrxR），一种含硒半胱氨酸的蛋白质和硫氧还蛋白系统的核心组成部分，是一个有前途的治疗靶点。倍半萜内酯化合物菜蓟苦素（Cynaropicrin，CYN）是菜蓟（Cynara scolymus L.）的主要成分，在许多实验模型中显示出多种药理作用，尤其是抗癌作用。这些功能中的大多数都伴随着活性氧（ROS）的产生。然而，这种有前途的天然抗癌产品在氧化还原控制中的靶点很少被探索。在这项研究中，我们发现CYN诱导Hela细胞凋亡。机制研究表明，CYN通过抑制TrxR影响硫氧还蛋白系统，导致HeLa细胞中Trx氧化和ROS积累。特别地，CYN的细胞毒性通过TrxR的基因敲低而增强，支持CYN的药理作用与其抑制TrxR有关。总之，我们的研究揭示了一个前所未有的机制占CYN的抗癌作用，并确定了一个有前途的治疗药物值得进一步发展的癌症治疗。
Cancer is considered as one of the highly mortal diseases globally. This is largely due to the lack of efficacious medicines for tumors, and thus development of potent anticancer agents is urgently needed. The thioredoxin (Trx) system is crucial to the survival ability of cells and its expression is up-regulated in many human tumors. Recently, increasing evidence has been established that mammalian thioredoxin reductase (TrxR), a seleno-cysteine-containing protein and the core component of the thioredoxin system, is a promising therapeutic target. The sesquiterpene lactone compound cynaropicrin (CYN), a major component of Cynara scolymus L., has shown multiple pharmacological functions, especially the anticancer effect, in many experimental models. Most of these functions are concomitant with the production of reactive oxygen species (ROS). Nevertheless, the target of this promising natural anticancer product in redox control has rarely been explored. In this study, we showed that CYN induces apoptosis of Hela cells. Mechanistic studies demonstrated that CYN impinges on the thioredoxin system via inhibition of TrxR, which leads to Trx oxidation and ROS accumulation in HeLa cells. Particularly, the cytotoxicity of CYN is enhanced through the genetic knockdown of TrxR, supporting the pharmacological effect of CYN is relevant to its inhibition of TrxR. Together, our studies reveal an unprecedented mechanism accounting for the anticancer effect of CYN and identify a promising therapeutic agent worthy of further development for cancer therapy.