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Journal of Environmental Pathology, Toxicology and Oncology
IF: 1.625 5-Year IF: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN Print: 0731-8898
ISSN Online: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvironPatholToxicolOncol.2017025229
pages 345-376

Dual Roles of Oxidative Stress in Metal Carcinogenesis

Jie Xu
Department of Anesthesiology, Beijing Chao Yang Hospital, Capital Medical University, No. 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China
James T. F. Wise
Division of Nutritional Sciences, Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
Lei Wang
Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
Kortney Schumann
Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
Zhuo Zhang
Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY
Xianglin Shi
Division of Nutritional Sciences, Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY; Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY; Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY

ABSTRACT

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.


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