Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy

Abstract

Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases, including cancers. Cancer cells have increased ROS levels compared with normal cells, because of their accelerated metabolism. The high ROS levels in cancer cells, which distinguish them from normal cells, could be protumorigenic, but are also their Achilles' heel. The high ROS content in cancer cells renders them more susceptible to oxidative stress-induced cell death, and can be exploited for selective cancer therapy. In this review, we describe several potential therapeutic strategies that take advantage of ROS imbalance in cancer cells by further increasing oxidative stress, either alone or in combination with drugs that modulate certain signaling pathways.

Figure 1. Cellular homeostasis of reactive oxygen species (ROS)

The major site of ROS generation inside the cells is the mitochondria. During respiration there is a leak of electrons to oxygen from complex I and complex III, which generates superoxide (O2^•−). The majority of superoxide is transferred to the mitochondrial matrix, where it is dismutated to hydrogen peroxide (H₂O₂) by the superoxide dismutase (SOD2). Some of the superoxide is transferred to the cytosol, where it is dismutated to H₂O₂ by the cytoslolic SOD1. ROS can be also generated by the activation of growth factor receptors, which in turn activate NADPH oxidase that oxidizes NADPH to generate superoxide. Hydrogen peroxide can then be detoxified by 3 major mechanisms: catalase, glutathione peroxidase (GPX) and peroxiredoxins (PRX). GPX and PRX detoxifying enzymes respectively utilize glutathione (GSH) and thioredoxins (Trx), generated by NADPH. IMM/OMM, Inner/Outer Mitochondrial Membrane; IMS, Inter Mitochondrial Space; PM, Plasma Membrane; MPTP, Mitochondrial Permeability Transition Pore; GR, Glutathione Reductase

Figure 2. Signaling pathways regulating intracellular ROS in cancer cells

A) Akt is activated by extracellular signals that activate PI3K. The tumor suppressor, PTEN is a phospho-lipid phosphatase that negates the activity of PI3K. Akt activation inhibits the FOXO transcription factors and activates mTOR Complex 1 (mTORC1). By increasing cellular metabolism Akt inhibits AMPK activity and increases the level of the by-products of energy metabolism, ROS. The inhibition of FOXOs by Akt inhibits the expression of anti-oxidants, which in turn further increase ROS levels. There is also interplay between FOXOs and mTORC1, whereby Sestrin3 induced by FOXOs activates AMPK and inhibits mTORC1. The activation of mTORC1 by Akt and by AMPK inhibition promotes several anabolic functions, but also elicits negative feedback loops that inhibit Akt. The high levels of FOXM1 in cancer cells could compensate for the suppression of FOXOs through induced expression of anti-oxidants genes. B) Energy stress during certain stages of tumor development increases oxidative stress by decreasing NADPH production through the pentose phosphate pathway (PPP). AMPK activation under energy stress conditions is required to maintain NADPH homeostasis and prevent oxidative stress induced cell death. AMPK activation inhibits the consumption of NADPH by fatty acid synthesis through the phosphorylation and inhibition of acetyl-coA carboxylase 1 (ACC1), and increases NADPH production via fatty acid oxidation, through phosphorylation and inhibition of ACC2.