Dual Roles of Oxidative Stress in Metal Carcinogenesis.
Dual Roles of Oxidative Stress in Metal Carcinogenesis.
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DOI：
10.1615/jenvironpatholtoxicoloncol.2017025229
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Shi X
中科院分区：
文献类型：
--
作者：
Xu J;Wise JTF;Wang L;Schumann K;Zhang Z;Shi X
众所周知，环境和职业暴露于重金属会导致多个器官的癌症。虽然重金属致癌的确切机制仍然难以捉摸，但金属产生的活性氧（ROS）是必不可少的。活性氧在金属致癌过程中可以发挥两种作用;金属致癌过程中的两个阶段在活性氧激活双重氧化还原介导的机制方面有所不同。在金属致癌的早期阶段，ROS起致癌作用。然而，在金属致癌的晚期阶段，ROS起着抗癌作用。同样，NF-E2相关因子2（Nrf 2）也具有两种不同的作用，这使其成为将金属致癌分为两个不同阶段的关键分子。在早期阶段，诱导型Nrf 2通过其抗氧化保护特性对抗升高的ROS以减少细胞转化。在晚期，组成性激活的Nrf 2操纵减少的ROS，通过致癌作用为细胞凋亡抗性提供舒适的环境。有趣的是，一种巧妙的致癌机制利用Nrf 2的双重作用，通过一系列氧化还原适应机制实现ROS的双重作用。在这篇综述中，我们讨论了这两个相反的ROS作用背后的理论基础的悖论，并专注于其潜在的药理学应用。ROS的双重作用代表了一把“双刃剑”，在金属致癌的癌症治疗中有许多可能的新的ROS介导的策略。
It has been well established that environmental and occupational exposure to heavy metal causes cancer in several organs. Although the exact mechanism of heavy metal carcinogenesis remains elusive, metal-generated reactive oxygen species (ROS) are essential. ROS can play two roles in metal carcinogenesis; two stages in the process of metal carcinogenesis differ in the amounts of ROS activating a dual redox-mediated mechanism. In the early stage of metal carcinogenesis, ROS acts in an oncogenic role. However, in the late stage of metal carcinogenesis, ROS plays an antioncogenic role. Similarly, NF-E2–related factor 2 (Nrf2) also has two different roles, which makes it a key molecule for separating metal carcinogenesis into two different stages. In the early stage, inducible Nrf2 fights against elevated ROS to decrease cell transformation by its antioxidant protection property. In the late stage, constitutively activated Nrf2 manipulates reduced ROS to perform a comfortable environment for apoptosis resistance through an oncogenic role. Interestingly, a cunning carcinogenic mechanism takes advantage of the dual role of Nrf2 to implement the dual role of ROS through a series of redox adaption mechanisms. In this review, we discuss the paradox in the rationales behind the two opposite ROS roles and focus on their potential pharmacological application. The dual role of ROS represents a ‘double-edged sword’ with many possible novel ROS-mediated strategies in cancer therapy in metal carcinogenesis.