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Review
. 2016 Jun 9;7(6):e2253.
doi: 10.1038/cddis.2016.105.

ROS homeostasis and metabolism: a dangerous liason in cancer cells

E Panieri  1 , M M Santoro  1   2   3
Affiliations
Review

ROS homeostasis and metabolism: a dangerous liason in cancer cells

E Panieri et al. Cell Death Dis. .

Abstract

Tumor cells harbor genetic alterations that promote a continuous and elevated production of reactive oxygen species. Whereas such oxidative stress conditions would be harmful to normal cells, they facilitate tumor growth in multiple ways by causing DNA damage and genomic instability, and ultimately, by reprogramming cancer cell metabolism. This review outlines the metabolic-dependent mechanisms that tumors engage in when faced with oxidative stress conditions that are critical for cancer progression by producing redox cofactors. In particular, we describe how the mitochondria has a key role in regulating the interplay between redox homeostasis and metabolism within tumor cells. Last, we will discuss the potential therapeutic use of agents that directly or indirectly block metabolism.

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Figures

Figure 1
Figure 1
ROS sources and scavengers in the control of redox homeostasis in normal and cancer cells. (a) Normal cells keep constant ROS production and elimination to maintain a favorable redox balance. Disruption of redox homeostasis by co-treatment with ROS inducers and antioxidant inhibitors induces oxidative stress and variable levels of cell death. (b) Cancer cells exhibit higher steady-state levels of ROS counterbalanced by increased antioxidant capacity. The combined use of pro-oxidizing treatment and antioxidant inhibition is expected to cause severe oxidative stress and severe cytotoxicity
Figure 2
Figure 2
Cellular metabolic pathway involved in redox homeostasis. Schematic representation of central metabolic pathways described in the text and involved in redox homeostasis. Metabolic pathway in the cytosol and mitochondria are represented. Metabolites in lowercase, enzymes in uppercase and inhibitors in red. Color code indicates metabolic pathways. FA fatty acids; HK, hexokinases; ROS, reactive oxygen species; PGD, phosphogluconate dehydrogenase; ME1, malic enzyme; a-KG, alpha ketoglutarate
Figure 3
Figure 3
Strategies to manipulate ROS levels as anticancer therapy. Effect of different therapeutic manipulations on the intracellular ROS levels and relative toxicity in both normal and cancer cells. (a) Normal cells treated with conventional chemo/radiotherapy, metabolic inhibitors or combined therapy show a slight increase in cell death. On the contrary treatment of cancer cells with (b) chemo/radiotherapy or (c) metabolic inhibitors elevates the rate of cell death compared with normal cells due to higher basal levels of ROS. When combined approaches on the basis of the use of metabolic inhibitors and conventional therapy (d) or other ROS-inducing agents can synergistically eradicate a larger proportion of cancer cells with marginal impact on normal cells, by elevating the intracellular ROS levels far above the toxicity threshold
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