Mitochondrial reactive oxygen species and cancer

Abstract

Mitochondria produce reactive oxygen species (mROS) as a natural by-product of electron transport chain activity. While initial studies focused on the damaging effects of reactive oxygen species, a recent paradigm shift has shown that mROS can act as signaling molecules to activate pro-growth responses. Cancer cells have long been observed to have increased production of ROS relative to normal cells, although the implications of this increase were not always clear. This is especially interesting considering cancer cells often also induce expression of antioxidant proteins. Here, we discuss how cancer-associated mutations and microenvironments can increase production of mROS, which can lead to activation of tumorigenic signaling and metabolic reprogramming. This tumorigenic signaling also increases expression of antioxidant proteins to balance the high production of ROS to maintain redox homeostasis. We also discuss how cancer-specific modifications to ROS and antioxidants may be targeted for therapy.

Keywords: Antioxidants; Cancer; Metabolism; Mitochondria reactive oxygen species; Oxidative stress; ROS.

Figure 1

Production and interconversion of reactive oxygen species. O₂ ^·− is formed from molecular O₂ by gaining a single electron from a NADPH oxidase (NOX) enzyme or from electron leak in the electron transport chain of the mitochondria. Superoxide dismutase (SOD) enzymes convert two superoxide molecules into a H₂O₂ and a water (H₂O) molecule. Hydrogen peroxide can undergo Fenton chemistry with Fe²⁺ to form HO^·, which is extremely reactive and can cause cellular damage. Hydrogen peroxide can also modify redox-sensitive cysteine residues to change cellular signaling. Alternatively, hydrogen peroxide can be reduced to water by glutathione peroxidases (GPXs), peroxiredoxins (PRXs), or catalase.

Figure 2

Balancing ROS generation and ROS scavenging allows cancer cells to remain in the tumorigenic range of ROS levels. Activation of mitochondrial ROS generation by oncogenes, mitochondrial mutations, hypoxia, or tumor suppressor loss increases ROS signaling to increase tumorigenicity. Tumor cells also express enhanced levels of antioxidant proteins that prevent increased ROS from reaching cytotoxic levels incompatible with growth.

Figure 3

Reactive oxygen species modify cellular signaling. Hydrogen peroxide derived from either NOXs or the mitochondria can activate the PI3K pathway, the hypoxia-inducible factor (HIF) pathway, and metabolic adaptations. These modifications are essential to allowing the survival, growth, and proliferation fundamental to tumorigenesis.

Figure 4

Pathways that modulate mitochondrial reactive oxygen species. Hypoxia, activation of oncogenes, mitochondrial DNA mutations, and loss of tumor suppressors have all been shown to lead to a mitochondrial ROS dependent increases in tumorigenesis.

Figure 5

Heteroplasmic mutations in mitochondrial DNA increase tumorigenesis. Small amounts of heteroplasmic mutations increase tumorigenicity by increasing mROS levels while maintaining mitochondrial biosynthetic capacity. However, large amounts of mtDNA mutations eventually compromise mitochondrial biosynthetic capacity and will decrease tumorigenicity.

Figure 6

Targeting cancer cells by modifying ROS levels. Normal cells have decreased amounts of both ROS and antioxidants relative to cancer cells. Loss of either ROS or antioxidants therefore causes only small changes in ROS homeostasis, leaving cells viable and functional. However, since cancer cells have more ROS and antioxidants, they may be more susceptible to changes in ROS levels. Treatment with antioxidants or prevention of ROS generation will cause cells to lose sufficient ROS signaling to maintain growth. The result is cytostasis and possibly senescence. Alternatively, inhibition of antioxidants or increasing ROS generation will result in excess ROS in cancer cells and cause cancer-specific oxidative cell death.