No abstract

Peroxiredoxins (Prxs) are antioxidant enzymes with ubiquitous expression in human tissues. Prxs are expressed in archaea, bacteria, and eukaryota, often in multiple isoforms. Because of their abundant expression in different cellular organelles and extraordinary sensitivity to H2O2, Prxs are among the first defenses against oxidative stress. Prxs undergo reversible oxidation to disulfides, and some family members perform chaperone or phospholipase functions upon further oxidation. Prxs are upregulated in cancer cells. Research has suggested that Prxs can function as tumor promoters in various cancers. The major objective of this review is to summarize novel findings regarding the roles of Prxs in common cancer types. Prxs have been shown to influence differentiation of inflammatory cells and fibroblasts, remodeling of extracellular matrix, and regulation of stemness. Since aggressive cancer cells have higher intracellular levels of ROS that they can utilize to proliferate and metastasize compared to normal cells, it is critical that we understand the regulation and functions of primary antioxidants such as Prxs. These small but mighty proteins could prove to be key for improving cancer therapeutics and patient survival.

No abstract

Peroxiredoxin IV (Prx4) is a 2-Cysteine peroxidase with ubiquitous expression in human tissues. Prx4 scavenges hydrogen peroxide and participates in oxidative protein folding in the endoplasmic reticulum. In addition, Prx4 is secreted outside the cell. Prx4 is upregulated in several cancers and is a potential therapeutic target. We have summarized historical and recent advances in the structure, function and biological roles of Prx4, focusing on inflammatory diseases and cancer. Oxidative stress is known to activate pro-inflammatory pathways. Chronic inflammation is a risk factor for cancer development. Hence, redox enzymes such as Prx4 are important players in the crosstalk between inflammation and cancer. Understanding molecular mechanisms of regulation of Prx4 expression and associated signaling pathways in normal physiological and disease conditions should reveal new therapeutic strategies. Thus, although Prx4 is a promising therapeutic target for inflammatory diseases and cancer, further research needs to be conducted to bridge the gap to clinical application.

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4−/− and Srx−/−/Prx4−/− mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients.