Redox metabolism and malignancy

Abstract

Redox balance underlies cellular homeostasis. Cancer initiation and progression has been linked to the disruption of redox balance and oxidative stress. Recent findings exemplify the distinctive roles of intracellular and extracellular redox state in the etiology and maintenance of oxidative stress associated with malignancy and metastasis. Within these compartments, redox sensitive cysteines play a crucial role in regulating cell signaling events that act to promote the malignant phenotype via the activation of survival pathways, disruption of cell-death signaling, and increases in cell proliferation. New approaches that aim to accurately evaluate subcellular and microenvironment redox potential may be useful in developing cancer diagnostics and therapeutics.

Figure 1

Accumulation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS), derived either endogenously or exogenously, results in oxidative stress. Disruption of thiol and non-radical circuits may also result in oxidative stress. The extent of this stress will either result in lethal damage and apoptosis or in cell adaptation. In cancer cells chronic oxidative stress activates redox sensitive transcription factors and signaling pathways that act to increase the expression of antioxidants, increase expression of survival factors as well inhibit the expression of pro-apoptotic pathways. ROS/RNS induced DNA injury promotes genomic instability and further provides opportunity to adapt to oxidative stress. Cancer progression occurs via the regulation of redox dependent expression of genes that play roles in proliferation, senescence evasion, metastasis, and angiogenesis. These features in association with the disruption in antioxidant profile may contribute to altered drug sensitivity and chemotherapy resistance. Definition of abbreviations: NOX, NADPH oxidase; nuclear factor-κB; NF-κB; Cys, cysteine; Cyss; cystine; GSH, glutathione; GSSH, glutathione disulfide, GSTP, glutathione-S-transferase P