Abstract
Reactive oxygen species (ROS) are a normal byproduct of cellular metabolism and are required components in cell signaling and immune responses. However, an imbalance of ROS can lead to oxidative stress in various pathological states. Increases in oxidative stress are one of the hallmarks in cancer cells, which display an altered metabolism when compared to corresponding normal cells. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide anion (O2−) in the extracellular environment. By doing so, this enzyme provides the cell with a defense against oxidative damage by contributing to redox balance. Interestingly, EcSOD expression has been found to be decreased in a variety of cancers, and this loss of expression may contribute to the development and progression of malignancies. In addition, recent compounds can increase EcSOD activity and expression, which has the potential for altering this redox signaling and cellular proliferation. This review will explore the role that EcSOD expression plays in cancer in order to better understand its potential as a tool for the detection, predicted outcomes and potential treatment of malignancies.
Highlights
Reactive oxygen species (ROS) are a normal byproduct of cellular metabolism that play a critical role in cell signaling processes, and are generated by enzyme systems as an integral part of innate immune responses [1,2]
A tissue array of 40 lung tumors of varying histology and grades demonstrated that Extracellular superoxide dismutase (EcSOD) mRNA expression was significantly decreased compared to normal lung tissue, and the level of EcSOD mRNA progressively decreased with advancing grade [37]
S.D. of each sample run in triplicate [37]
Summary
Factors affecting the regulation of EcSOD expression are numerous and varied. Some of the major factors include nitric oxide, which can be inactivated by superoxide anion and has been shown to upregulate EcSOD in a mouse model [23]. EcSOD expression in human dermal fibroblasts and vascular smooth muscle cells. In both cell types, IFN-γ increased, whereas TNFα decreased the expression of EcSOD [26]. TGFβ decreased EcSOD in fibroblasts, whereas IL-4 increased EcSOD in smooth muscle cells [12,26]. In rat vascular smooth muscle cells, as well as in human monocytes, treatment with estrogen significantly increased. Copper, which is a required cofactor for EcSOD activity, has been demonstrated to positively regulate EcSOD transcription, leading to increased EcSOD mRNA and protein. This effect is mediated through the copper chaperone Antioxidant1 [28]
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