The Role of Peroxiredoxins in Cancer Development

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.

Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence

“…As a pro-oxidative phytochemical, two mechanisms have been reported for ROS induction by celastrol: (1) inhibition of mitochondrial respiratory chain complex I activity [ 80 ]; and (2) inhibition of peroxiredoxins, namely peroxiredoxin-1 [ 76 ] and peroxiredoxin-2 [ 78 ]. The latter is thought to be the main mechanism of action, given that peroxiredoxins are upregulated in many cancer types and are involved in tumorigenesis and chemoresistance [ 83 , 84 , 85 ]. Consequently, celastrol derivatives are currently in development to improve their potency and specificity against peroxiredoxins [ 76 ].…”

Pitfalls of Mitochondrial Redox Signaling Research

“…They form a toroid (doughnut-like) structure of five (six) homodimers, which can split from the toroid in an unstable disulfide conformation ( Figure 3 ). The second resolving cysteine, C R , in the second homodimer subunit forms an inter-subunit disulfide bond with C P upon a reaction with H 2 O 2 [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. At first, sulfenic acid (R-SOH) is formed via two-electron reversible oxidation.…”

“…Since peroxiredoxins react with H 2 O 2 faster than other peroxidases, such as catalases and glutathione peroxidases (GPX), they are considered as the main regulators of cytosolic H 2 O 2 (besides NOX enzymes) and the related development of diseases with etiology involving oxidative stress. Thus, peroxiredoxins have been implicated in cancer development [ 49 , 50 ], as targets for cardiovascular disease [ 51 ] or neurodegenerative diseases [ 52 ], and in the β-cell defense against oxidative damage [ 53 ].…”

“…In human cells, six isoforms of PRDXs exist. PRDX1, PRDX2, and PRDX6 are localized in the cytosol and nucleus, while PRDX4 is localized in the endoplasmic reticulum [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. The isoform PRDX3 is exclusively mitochondrial, whereas PRDX5 is located in mitochondria [ 64 ], but also in the cytosol and peroxisomes.…”

Gender Differences in Oxidative Stress in Relation to Cancer Susceptibility and Survival

“…Moreover, the activation of oncogenes such as RAS2 or c-Myc is one example of a disorder in cellular signaling that is thought to be a significant generator of ROS [ 11 , 12 ]. For cells, oxidative stress may be damaging, but intrinsic oxidative stress in cancer cells in malignant neoplasms may have dramatic effects, including cancer cell proliferation, the promotion of genetic instability, and changes in cellular sensitivity to anticancer agents, and the modulation of cellular redox parameters is a real possibility [ 13 , 14 , 15 , 16 , 17 , 18 ] ( Figure 1 ).…”