Peroxiredoxin, Senescence, and Cancer

Abstract

Peroxiredoxins are multifunctional enzymes that play a key role in protecting cells from stresses and maintaining the homeostasis of many cellular processes. Peroxiredoxins were firstly identified as antioxidant enzymes that can be found in all living organisms. Later studies demonstrated that peroxiredoxins also act as redox signaling regulators, chaperones, and proinflammatory factors and play important roles in oxidative defense, redox signaling, protein folding, cycle cell progression, DNA integrity, inflammation, and carcinogenesis. The versatility of peroxiredoxins is mainly based on their unique active center cysteine with a wide range of redox states and the ability to switch between low- and high-molecular-weight species for regulating their peroxidase and chaperone activities. Understanding the molecular mechanisms of peroxiredoxin in these processes will allow the development of new approaches to enhance longevity and to treat various cancers. In this article, we briefly review the history of peroxiredoxins, summarize recent advances in our understanding of peroxiredoxins in aging- and cancer-related biological processes, and discuss the future perspectives of using peroxiredoxins in disease diagnostics and treatments.

Keywords: DNA integrity; aging; cancer; carcinogenesis; chaperone; cycle cell progression; inflammation; oxidative defense system; peroxiredoxin; redox signaling.

Figure 1

Schematic illustration of the general functions of peroxiredoxins. The highly conserved redox-sensitive cysteine residue (peroxidatic cysteine) in peroxiredoxin directly reduces various peroxide substrates (ROOH). A resolving cysteine can regenerate the peroxide reduction activity of the peroxidatic cysteine by thioredoxin (Trx)/thioredoxin reductase (TrxR)/nicotinamide adenine dinucleotide phosphate (NADPH) system. The peroxidase activity of peroxiredoxin can be easily inactivated by hyperoxidation of the peroxidatic cysteine to cysteine sulfinic acid (Cys-SO_2⁻). A special oxidoreductase sulfiredoxin (SRX) is required to restore the peroxidase activity of hyperoxidized peroxiredoxins by reducing sulfinic acid of peroxiredoxin back to thiol in an ATP-dependent manner. Interestingly, hyperoxidated peroxiredoxin is required for the recruitment of cytosolic molecular chaperone HSP70 and disaggregase HSP104 to rescue misfolded proteins from aggregates. Extracellular peroxiredoxins function as DAMPs by triggering a proinflammatory response via binding to TLR2/TLR4 receptor.