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Review
. 2016 Jul:163:1-23.
doi: 10.1016/j.pharmthera.2016.03.018. Epub 2016 Apr 26.

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

Mi Hee Park  1 , MiRan Jo  1 , Yu Ri Kim  1 , Chong-Kil Lee  2 , Jin Tae Hong  3
Affiliations
Review

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

Mi Hee Park et al. Pharmacol Ther. 2016 Jul.

Abstract

Peroxiredoxins (PRDXs) are antioxidant enzymes, known to catalyze peroxide reduction to balance cellular hydrogen peroxide (H2O2) levels, which are essential for cell signaling and metabolism and act as a regulator of redox signaling. Redox signaling is a critical component of cell signaling pathways that are involved in the regulation of cell growth, metabolism, hormone signaling, immune regulation and variety of other physiological functions. Early studies demonstrated that PRDXs regulates cell growth, metabolism and immune regulation and therefore involved in the pathologic regulator or protectant of several cancers, neurodegenerative diseases and inflammatory diseases. Oxidative stress and antioxidant systems are important regulators of redox signaling regulated diseases. In addition, thiol-based redox systems through peroxiredoxins have been demonstrated to regulate several redox-dependent process related diseases. In this review article, we will discuss recent findings regarding PRDXs in the development of diseases and further discuss therapeutic approaches targeting PRDXs. Moreover, we will suggest that PRDXs could be targets of several diseases and the therapeutic agents for targeting PRDXs may have potential beneficial effects for the treatment of cancers, neurodegenerative diseases and inflammatory diseases. Future research should open new avenues for the design of novel therapeutic approaches targeting PRDXs.

Keywords: Cancer; Inflammatory diseases; Neurodegenerative diseases; Peroxiredoxins; Therapeutic approaches.

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Figures

Fig. 1
Fig. 1
General functions of PRDXs. Mechanism of action of the PRDX redox system. PRDXs scavenge H2O2 and become oxidized and inactive. PRDXs use the SH groups as reducing equivalents. This inactivation is reversed by the thioredoxin (Trx)-Trx reductase (TrxR) system that uses NADPH as reducing equivalents. Reduced Trx catalyzes the reduction of disulphides (s-s) within oxidized PRDXs. The oxidized form of PRDXs can then be recycled back to its reduced form by Trx. Further thiol oxidation of PRDXs by higher levels of H2O2 radically inactivates the target proteins allowing H2O2 levels to increase in the cell and to trigger the H2O2-dependent signaling. This inactivation is transient to avoid toxic effects by high levels of H2O2.
Fig. 2
Fig. 2
Cellular localization and roles of PRDXs. Tyrosine residue of PRDX1 is phosphorylated, which causes the transient inactivation of peroxidase activity. As a result, a local accumulation of H2O2 occurs and sustains phosphorylation signaling from tyrosine kinase for the growth factor receptor via the oxidative inactivation of phosphotyrosine phosphatases. Consequently the cell growth proceeds for a prolonged period as the result of the elevated H2O2 during the inactivation of PRDX1. PRDX2 is localized in the cytosol and scavenges ROS in the cytosol and blocks Bax mediated cell death by inhibition of cellular apoptosis. PRDX3 is localized in the mitochondria. PRDX3 reduces H2O2 level and protects cells from oxidative damages. PRDX4 possesses a hydrophobic N-terminal signal peptide that leads to its secretion from cells and predominant localization in the ER. PRDX5 reduces H2O2 and alkyl hydroperoxides that acts as antioxidant on different tissues under normal conditions and inflammatory processes through Trx system in peroxisomes. PRDX6 involved in redox regulation of the cell and can reduce H2O2 and short chain organic, fatty acid, and phospholipid hydroperoxides. PRDX6 plays a role in the regulation of phospholipid turnover as well as in the protection against oxidative injury.
Fig. 3
Fig. 3
General regulatory pathway of PRDX expression. Nrf2 induces the expression of PRDXs in response to oxidative and electrophilic stresses. Under unstressed conditions, Nrf2 is degraded via the ubiquitin (Ub)–proteasome pathway in a Keap1-dependent manner. The Keap1 homodimer binds a single Nrf2 molecule through two-site binding utilizing the DLG and ETGE motifs. When Nrf2 inducers inactivate Keap1 via the modification of cysteine residues (Cys) under oxidative stress and electrophiles modified condition, Nrf2 is stabilized, and de novo synthesized Nrf2 translocates into the nucleus. Nrf2 heterodimerizes with small Maf proteins (sMaf) and activates the expression of target genes including PRDXs through antioxidant response elements (AREs), exerting cytoprotective effects against various diseases and toxic insults. Phosphorylation of Nrf2 by various kinases has also been implicated in the liberation, stability, and trans-activation of Nrf2.
Fig. 4
Fig. 4
Signaling pathway related with cancer development. PRDX1 enhances the transactivation potential of NF-κB in ER-deficient breast cancer cells and upregulates phosphorylation of NF-κB subunit in bladder cancers. PRDX1 promotes tumorigenesis of esophageal squamous cell carcinoma through regulating the activity of mTOR/p70S6K pathway. PRDX2 is involved in the regulation of Wnt/β-catenin signaling in colorectal cancer cells. Specifically, PRDX2 inhibits GSK-3β activity, enhances β-catenin translocation into the nucleus, and inhibits the levels of β-catenin phosphorylation, thus resulting in significant up-regulation of transcription of the LEF/TCF target genes c-Myc and Survivin. PRDX3 is associated with NF-κB signaling pathway. PRDX3 enhances I-κB phosphorylation and induces NF-κB signaling pathway. PRDX3 also acts synergistically with MAP3K13 to regulate the activation of NF-κB in the cytosol. PRDX4 binds with Srx and the Srx-PRDX4 axis contributes to the maintenance of lung tumor phenotype by AP-1 and MAPK signaling pathway. PRDX6 promotes tumor development via the JAK2/STAT3 pathway in a urethane-induced lung tumor model. Upregulation of PRDX6 results in the activation of Akt via PI3K and p38 kinase.
Fig. 5
Fig. 5
Possible mechanisms of PRDXs related with neurodegenerative disease. ROS mediate neurotoxicity of AD through modifying the hallmark protein by oxidation. In AD, ROS could also activate c-Jun N-terminal kinases (JNK) and p38, and deactivate protein phosphatase 2A (PP2A). JNK and p38 promote the expression of Tau, which is inhibited by PP2A. The activation of JNK and p38 further stimulate APP cleaving enzyme 1 (BACE1), causing Aβ1-42 accumulation, which leads to activation of NADPH oxidase (Nox) to produce additional O2, and results in Ca2 + influx to elicit excitatory neurotoxicity. PRDX2 inhibits the generation and accumulation of Aβ1-42, and protects the brain from AD neurotoxicity. PRDX6 accelerates cell dysfunction and cell death proceeded from ROS generation. In PD, the α-Syn is aggregated and generates ROS that also generated from Ca2 + accumulation. PRDX5 induces the Ca2 + accumulation that can cause ROS generation. PRDX2 and PRDX5 mediate the neurotoxicity through induction of cell dysfunction and cell death from ROS accumulation. PD is also generated from LRRK2 mutation. This mutation causes PRDX3 phosphorylation, after that ROS accumulates, resulting in cellular dysfunction and cellular death.
Fig. 6
Fig. 6
Possible mechanisms of PRDXs related with inflammatory disease. PRDX1 can induce activation of NF-κB through TLR4. PRDX1 is secreted from cells under mild oxidative stress and binds with TLR4 which results in induced NF-κB activation that is important for the expression of inflammatory proteins. Recombinant PRDX1 supplemented to the culture medium induced secretion of TNF-α and IL-6 from mouse thioglycolate-elicited peritoneal macrophages and BMDM. This effect of PRDX1 is quite similar to that of LPS as it required membrane proteins CD14 and MD2 and was mediated by the TLR4-MyD88 signaling leading to the activation of NF-κB. It was speculated that PRDXs released from necrotic cells induce NF-κB activation and the production of IL-23. PRDX2 is a negative regulator of PDGF signalling. PRDX2 suppresses activation of PDGF receptor (PDGFR) and phospholipase Cγ1, and subsequently decreases cell proliferation and migration in response to PDGF. Also, PRDX2 is recruited to PDGFR upon PDGF stimulation, and suppresses protein tyrosine phosphatase inactivation. PRDX5 and PRDX6 are TLR4-dependent inducers of infiltrating macrophage activation and the subsequent production of inflammatory mediators from invading T cells in the ischemic brain. Overexpression of PRDX6 promotes development of RA through activation of NF-κB/AP-1 coupled with JNK pathway in the CAIA and AIA-induced arthritis development model.
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