Oxidative Stress Induced by MnSOD-p53 Interaction: Pro- or Anti-Tumorigenic?

Abstract

The formation of reactive oxygen species (ROS) is a result of incomplete reduction of molecular oxygen during cellular metabolism. Although ROS has been shown to act as signaling molecules, it is known that these reactive molecules can act as prooxidants causing damage to DNA, proteins, and lipids, which over time can lead to disease propagation and ultimately cell death. Thus, restoring the protective antioxidant capacity of the cell has become an important target in therapeutic intervention. In addition, a clearer understanding of the disease stage and molecular events that contribute to ROS generation during tumor promotion can lead to novel approaches to enhance target specificity in cancer progression. This paper will focus on not only the traditional routes of ROS generation, but also on new mechanisms via the tumor suppressor p53 and the interaction between p53 and MnSOD, the primary antioxidant enzyme in mitochondria. In addition, the potential consequences of the p53-MnSOD interaction have also been discussed. Lastly, we have highlighted clinical implications of targeting the p53-MnSOD interaction and discussed recent therapeutic mechanisms utilized to modulate both p53 and MnSOD as a method of tumor suppression.

Figure 1

p53 Multifunctional domains. The p53 monomer consists of various multifunctional domains including the N-terminal transactivation domain (residues 1–73), a proline-rich region (residues 63–97), the highly conserved DNA-binding core domain (residues 94–312), a tetramerization domain located within the C-terminus (residues 324–355), and an unstructured basic domain (residues 360–393).

Figure 2

Mechanisms of carcinogens in early stage carcinogenesis. During the early stages of tumor promotion both oncogenes and tumor suppressor genes are activated, resulting in increased cell proliferation being accompanied by increased cell death.

Figure 3

Mechanism involving the p53-MnSOD interaction during the early stage of tumor promotion. Following exposure to a carcinogen the Ras-Rac1-NADPH oxidase pathway is activated, which leads to p53 mitochondrial translocation. Mitochondrial p53 has been shown to interact with MnSOD, resulting in decreased enzymatic activity and promoting oxidative stress propagation contributing to the early stage of skin tumorigenicity. Elevated levels of MnSOD reduced oxidative stress propagation, suppressed p53 mitochondrial translocation, and decreased downstream skin tumor formation. Reduced levels of MnSOD have been shown to contribute to oxidative stress propagation and promote early-stage skin tumorigenicity.