Respiratory control of redox signaling and cancer

In the past several decades, elegant work has been performed in a variety of organisms suggesting that decreases in oxidant burden can prolong life span and decrease the severity of age-associated degenerative disorders (Finkel T, Holbrook NJ. Nature 2000; 408:239-247). Cancer is primarily an age-related disease and is associated with the altered production of oxidants (Cerutti PA. Science 1985; 227:375-381). Compounds that generate reactive oxygen species (ROS) promote skin tumors in mice. Treatment with antioxidants that terminate the chain reactions initiated by ROS antagonizes this process. Many tumor cell types have also been shown to have an increased oxidant radical load relative to normal tissue. Thus, tumor cells have adapted to cope with an increased oxidant burden compared with that of normal nonmalignant tissue and may even harness the increased oxidant load to modulate signaling pathways that are critical for their survival. With the tight connection between oxidant production and tumor promotion and growth, it is quite surprising that antioxidant-based therapeutics have not become pervasive in treatments for many cancers (for a concise review on this topic, see Seifried HE, et al. Cancer Research 2003; 63:4295-4298). Hydrogen peroxide (H₂O₂) is the electron-neutral, 2e ^- reduction product of oxygen that is generated both chemically and enzymatically and can modulate the activity of a variety of signaling molecules. This chapter will summarize how the metabolic production of H₂O ₂ can impact distinct signaling pathways that are essential for successful tumorigenesis and metastatic progression and will identify redox-sensitive pathways that may be targets for antioxidant-based cancer therapy.