Curcumin targeting the thioredoxin system elevates oxidative stress in HeLa cells
Curcumin targeting the thioredoxin system elevates oxidative stress in HeLa cells
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姜黄素靶向硫氧还蛋白系统可提高 HeLa 细胞的氧化应激
DOI：
10.1016/j.taap.2012.05.012
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发表时间：
2012-08-01
影响因子：
3.8
通讯作者：
Fang, Jianguo
中科院分区：
文献类型：
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作者：
Cai, Wenqing;Zhang, Baoxin;Fang, Jianguo
硫氧还蛋白系统由硫氧还蛋白还原酶（TrxR）、硫氧还蛋白（Trx）和NADPH组成，在所有细胞中普遍存在，并参与许多氧化还原依赖的信号通路。姜黄素是一种天然存在的色素，在咖喱食物中呈现特定的黄色，在正常饮食中每天消耗高达100毫克。这种分子也被用于传统医学中治疗各种疾病。姜黄素具有多种生物学功能，其中许多功能与诱导氧化应激有关。然而，姜黄素如何消除细胞中的氧化应激尚不清楚。我们以前的工作已经证明了姜黄素与重组TrxR 1相互作用的方式，并在体外将抗氧化酶改变为活性氧（ROS）发生器。在此，我们报道了姜黄素可以靶向细胞质/核硫氧还蛋白系统，最终提高HeLa细胞的氧化应激。姜黄素修饰的TrxR 1剂量依赖性和定量地将电子从NADPH转移到氧，产生ROS。此外，姜黄素可以大幅下调Trx 1蛋白水平以及其在HeLa细胞中的酶活性，这反过来又显着减少细胞内游离巯基，将细胞内氧化还原平衡转移到更氧化的状态，并随后诱导DNA氧化损伤。此外，姜黄素预处理的HeLa细胞对氧化应激更敏感。TrxR 1的敲低使HeLa细胞对姜黄素的细胞毒性敏感，突出了姜黄素靶向TrxR 1的生理意义。总之，我们的数据揭示了姜黄素在细胞中的一种以前未被认识到的促氧化机制，并为了解姜黄素在体内的作用机制提供了深刻的见解。(C)2012 Elsevier Inc. All rights reserved.
The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, is ubiquitous in all cells and involved in many redox-dependent signaling pathways. Curcumin, a naturally occurring pigment that gives a specific yellow color in curry food, is consumed in normal diet up to 100 mg per day. This molecule has also been used in traditional medicine for the treatment of a variety of diseases. Curcumin has numerous biological functions, and many of these functions are related to induction of oxidative stress. However, how curcumin elicits oxidative stress in cells is unclear. Our previous work has demonstrated the way by which curcumin interacts with recombinant TrxR1 and alters the antioxidant enzyme into a reactive oxygen species (ROS) generator in vitro. Herein we reported that curcumin can target the cytosolic/nuclear thioredoxin system to eventually elevate oxidative stress in HeLa cells. Curcumin-modified TrxR1 dose-dependently and quantitatively transfers electrons from NADPH to oxygen with the production of ROS. Also, curcumin can drastically down-regulate Trx1 protein level as well as its enzyme activity in HeLa cells, which in turn remarkably decreases intracellular free thiols, shifting the intracellular redox balance to a more oxidative state, and subsequently induces DNA oxidative damage. Furthermore, curcumin-pretreated HeLa cells are more sensitive to oxidative stress. Knockdown of TrxR1 sensitizes HeLa cells to curcumin cytotoxicity, highlighting the physiological significance of targeting TrxR1 by curcumin. Taken together, our data disclose a previously unrecognized prooxidant mechanism of curcumin in cells, and provide a deep insight in understanding how curcumin works in vivo. (C) 2012 Elsevier Inc. All rights reserved.