Xu Jie, Wise James T F, Wang Lei, Schumann Kortney, Zhang Zhuo, Shi Xianglin
Department of Anesthesiology, Beijing Chao Yang Hospital, Capital Medical University, No. 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China.
Division of Nutritional Sciences, Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
J Environ Pathol Toxicol Oncol. 2017;36(4):345-376. doi: 10.1615/JEnvironPatholToxicolOncol.2017025229.
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.
环境和职业性接触重金属会导致多个器官发生癌症，这一点已经得到充分证实。尽管重金属致癌的确切机制仍不清楚，但金属产生的活性氧（ROS）至关重要。ROS在金属致癌过程中可发挥两种作用；金属致癌过程的两个阶段在激活双氧化还原介导机制的ROS量方面有所不同。在金属致癌的早期阶段，ROS发挥致癌作用。然而，在金属致癌的后期阶段，ROS发挥抗癌作用。同样，NF-E2相关因子2（Nrf2）也有两种不同的作用，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Nrf2通过其抗氧化保护特性对抗升高的ROS，以减少细胞转化。在后期阶段，组成型激活的Nrf2通过致癌作用操纵减少的ROS，为抗凋亡创造适宜环境。有趣的是，一种巧妙的致癌机制利用Nrf2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ROS两种相反作用背后原理中的矛盾之处，并重点关注它们潜在的药理学应用。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型ROS介导策略。
