Dual roles of oxidative stress in metal carcinogenesis

Jie Xu, James T.F. Wise, Lei Wang, Kortney Schumann, Zhuo Zhang, Xianglin Shi

Research output: Contribution to journalReview articlepeer-review

48 Scopus citations


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.

Original languageEnglish
Pages (from-to)345-376
Number of pages32
JournalJournal of Environmental Pathology, Toxicology and Oncology
Issue number4
StatePublished - 2017

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (grant nos. R01ES021771, R01ES025515, R01ES020870, and R01ES017244).

Publisher Copyright:
© 2017, Begell House Inc.


  • Carcinogenesis
  • Metal
  • Oxidative stress
  • Reactive oxygen species (ROS)
  • Redox adaptation
  • Tumorigenesis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Toxicology
  • Health, Toxicology and Mutagenesis


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