From Cytoprotection to Tumor Suppression: The Multifactorial Role of Peroxiredoxins

Abstract

In the past decade, a new family of highly conserved antioxidant enzymes, Peroxiredoxins (Prxs), have been discovered and defined. There are two major Prx subfamilies: one subfamily uses two conserved cysteines (2-Cys) and the other uses 1-Cys to scavenge reactive oxygen species (ROS). This review focuses on the four mammalian 2-Cys members (Prx I-IV) that utilize thioredoxin as the electron donor for antioxidation. The array of biological activities of these proteins suggests that they may be evolutionarily important for cell function. For example, Prxs are capable of protecting cells from ROS insult and regulating the signal transduction pathways that utilize c-Abl, caspases, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) to influence cell growth and apoptosis. Prxs are also essential for red blood cell (RBC) differentiation and are capable of inhibiting human immunodeficiency virus (HIV) infection and organ transplant rejection. Distribution patterns indicate that Prxs are highly expressed in the tissues and cells at risk for diseases related to ROS toxicity, such as Alzheimer's and Parkinson's diseases and atherosclerosis. This interesting correlation suggests that Prxs are protective against ROS toxicity, yet overwhelmed by oxidative stress in some cells. Prxs tend to form large aggregates at high concentrations, a feature that may interfere with their normal protective function or may even render them cytotoxic. Imbalance in the expression of subtypes can also potentially increase their susceptibility to oxidative stress. Understanding the function and biological role of Prxs may lead to important discoveries about the cellular dysfunction of ROS-related diseases ranging from atherosclerosis to cancer to neurodegenerative diseases.

A mosquito 2-Cys peroxiredoxin protects against nitrosative and oxidative stresses associated with malaria parasite infection

“…In addition to direct detoxification, however, AsPrx-4783 may also mediate cellular responses to ROS and RNOS indirectly. Specifically, 2-Cys Prx can regulate several proteins and pathways that regulate apoptotic cell death directly, including the tyrosine kinase c-Abl, caspases, nuclear factor-κB, and activator protein-1 [35]. In addition, the human 2-Cys PrxII can alternate between functioning as a peroxidase and functioning as a protein chaperone to protect HeLa cells from hydrogen peroxide-induced cell death [68].…”

“…In organisms ranging from yeast to insects to human cells, Prx gene silencing has resulted in decreased cell survival when deficient cells are exposed to toxic oxidative and nitrosative stress [4,14,35]. Therefore, to provide additional supporting data that AsPrx-4783 protected A. stephensi cells against ROS-and RNOS-associated damage, we used dsRNA-mediated RNA interference to silence AsPrx-4783 expression in A. stephensi cells.…”

Induction of radioprotective peroxiredoxin‐I by ionizing irradiation

“…Another possible explanation is that, in our study, we used monoclonal antibodies specific for human Prx-I and -II, whereas Park et al used polyclonal antibodies for their detection of Prx-II. Because Prx-I and -II have extensive domains with identical amino acid sequences (Butterfield et al, 1999), it is possible that the polyclonal antibodies that were used by Park et al detected Prx-I as well as Prx-II. In any event, the results from Park et al and from our study together strongly indicate a role for Prxs in radiation responses.…”

“…Recently, a new family of highly conserved antioxidant enzymes, peroxiredoxins (Prxs), has been discovered and characterized Rhee et al, 1994;Butterfield et al, 1999). There are two major Prx subfamilies.…”

“…Park et al recently showed that levels of human Prx-II were associated with resistance of cells to radiation therapy and that Prx-II antisense served as a radiosensitizer (Park et al, 2000). Prx-I shares high sequence homology with Prx-II, with similar antioxidative and antiapoptotic functions (for review see Butterfield et al, 1999). However, some activities observed in Prx-I, such as cAbl kinase inhibition (Prospaeri et al, 1998), heme binding (Nakaso et al, 2000), and natural killer enhancement (Sauri et al, 1996), have not been reported for Prx-II.…”