Cancer Letters

Cancer Letters

Volume 286, Issue 2, 28 December 2009, Pages 154-160
Cancer Letters

Mini-review
Peroxiredoxins, a novel target in cancer radiotherapy

https://doi.org/10.1016/j.canlet.2009.04.043Get rights and content

Abstract

Reactive oxygen species (ROS) are toxic at high levels in the mammalian cells. Mammalian cells have developed many enzymatic and nonenzymatic antioxidative systems in various cellular compartments to maintain an appropriate level of ROS and regulate their action. Peroxiredoxins (Prxs), a family of peroxidase that reduced intracellular peroxides (one type of ROS) with the thioredoxin system as the electron donor, were highly expressed in various cellular compartments. In this minireview, we discussed the regulation of Prxs expression in cancer cell and its relationship with ionizing radiation. As Prxs could be induced by radiation and its expression status could determine the radiosensitivity of cancer cells, Prxs might be a potential target for radiotherapy in cancer.

Introduction

Reactive oxygen species (ROS) are toxic at high levels in the mammalian cells, which can be derived from physical or chemical stimulus. Peroxides belong to ROS and H2O2 is one of the peroxides. They are usually more reactive than the corresponding non-radicals because they can act as oxidizing agents. Endogenous ROS are usually by-products of cellular metabolism, and can be induced to high level. Though ROS cause cellular damages, recent studies found H2O2 signaling is associated with the signal transduction of growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), and required for subsequent protein tyrosine phosphorylation. This indicated cellular H2O2 might be a new kind of messenger and is stringently controlled in mammalian cells [1]. ROS are conventionally considered to have carcinogenic potential and to promote invasiveness. In order to maintain an appropriate level of ROS and regulate their action, mammalian cells have developed many enzymatic and nonenzymatic antioxidative systems in various cellular compartments. The enzymatic systems include catalase, superoxide dismutase, and glutathione-dependent peroxidase, and the recently characterized peroxiredoxins (Prxs). The presence of all these enzymes creates a complex network of peroxidases. Prxs, a well-defined family of highly conserved antioxidant enzymes, has been discovered and shown to play an important role in peroxide detoxification [2], [3].

The important physical stimulus that causes ROS is ionizing radiation (IR). IR is one of the main treatment modalities used in the management of cancer, and it can evoke a series of biochemical events inside of the cell. These events include many important cellular processes, such as DNA damage and repair, apoptosis, cell cycle control, signal transduction, and oxidative stress response [4], [5]. IR can act directly and indirectly. The direct effect includes damage of DNA and proteins by the energy of radiation and by the reactive oxygen species (ROS) derived from intercellular water. The indirect effect is the secondary response involved in signal transduction and gene expression. Among these effects, ROS induced by IR is crucial for cell survival. The mechanisms of ROS induced by IR involved in cell death especially in the induction of apoptotic death, which were widely investigated in the field of cancer radiotherapy. The deleterious effects by ROS include DNA damage and membrane oxidative damage. The formation of single and/or double stranded breaks of DNA resulted in cell cycle arrest and recruitment of DNA repair enzymes to rescue cells from the damage. Mammalian cells have developed complicated antioxidant systems to deal with the oxidative stress. In this minireview, we will focus on the regulation of Prxs and its potentiality as a target of radiotherapy in cancer.

Section snippets

Genomic structures

The first member of this family was discovered as a 27-kDa protein in yeast [6]. Different from catalase, glutathione peroxidase, superoxide dismutase, or iron chelation activities, its protection activity was specific for mixed-function oxidation systems containing thiols, and its expression was induced by oxidative stress. Since then, Prxs have been identified in many organisms and constitute a ubiquitous family of thiol-dependent peroxidases catalyzing the reduction of hydrogen peroxide.

Aberrant regulations of Prxs in cancer

The process of transformation and tumorigenesis is accompanied by cumulative mutations in genetic pathways that confer a growth advantage of cancer. So this process is thought to be involved with many genes (e.g. oncogenes and tumor suppressors) and is a result of multistage of mutagenesis. The most outstanding biochemical function of Prxs is to reduce peroxide. Oxidative stress and damage by free radicals have been showed involved in tumorigenesis. ROS is conventionally considered to have

Radiotherapy of cancer based on Prxs

As IR can induce cellular ROS that can be eliminated by Prxs, it is much attractive to study the relationship between IR and Prxs expression. Induction of Prxs expression has been found in many types of mammalian cells. Moreover, the expression status of Prxs is one of the main factors that influence the radiation effects. For cancer radiotherapy, silencing of Prxs expression is currently tested to enhance the radiotherapy effect.

Concluding remarks

The functions of Prxs include not only detoxification of peroxide, but also increase of cell survival and proliferation. Its protection is important for both non-malignant and malignant cells against oxidants, radiation and chemotherapies. The functional significance is still unresolved and waits future studies. New findings about its functions are accumulating day by day. Prxs are expressed not only in tumor cells but also in various nonmalignant cells. Though highly expressed Prxs in

Conflict of interest

We confirm that all authors have not any financial and personal relationships with other people or organizations that could inappropriately influence our work.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 30772146), “973” programs from the Ministry of Science and Technology of China (No. 2005CB522605), and Innovation Group of Education Ministry (Grant No. IRI0712).

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