Peroxiredoxin 1 - an antioxidant enzyme in cancer

Abstract

Peroxiredoxins (PRDXs), a ubiquitous family of redox-regulating proteins, are reported of potential to eliminate various reactive oxygen species (ROS). As a major member of the antioxidant enzymes, PRDX1 can become easily over-oxidized on its catalytically active cysteine induced by a variety of stimuli in vitro and in vivo. In nucleus, oligomeric PRDX1 directly associates with p53 or transcription factors such as c-Myc, NF-κB and AR, and thus affects their bioactivities upon gene regulation, which in turn induces or suppresses cell death. Additionally, PRDX1 in cytoplasm has anti-apoptotic potential through direct or indirect interactions with several ROS-dependent (redox regulation) effectors, including ASK1, p66^Shc , GSTpi/JNK and c-Abl kinase. PRDX1 is proven to be a versatile molecule regulating cell growth, differentiation and apoptosis. Recent studies have found that PRDX1 and/or PRDX1-regulated ROS-dependent signalling pathways play an important role in the progression and metastasis of human tumours, particularly in breast, oesophageal and lung cancers. In this paper, we review the structure, effector functions of PRDX1, its role in cancer and the pivotal role of ROS in anticancer treatment.

Keywords: cancer; peroxiredoxin 1; reactive oxygen species.

Figure 1

The roles of cytoplasm PRDX1 in the oxidative stress‐induced apoptosis. PRDX1 cooperates with Trx in suppressing H₂O₂‐induced cell death involving different types of kinases and enzymes, such as ASK1, p66^Shc and GSTpi/JNK. In addition, PRDX1 could inhibit JNK and p38 MAPK‐induced cell apoptosis through direct interaction with c‐Abl tyrosine kinase under oxidative stress conditions. Notably, PRDX1 prevents Akt‐driven tumourigenesis and then promotes cell apoptosis through protecting PTEN lipid phosphatase activity from oxidation‐induced inactivation.

Figure 2

The roles of nucleus PRDX1 in the H₂O₂‐induced apoptosis. It is also known that PRDX1 functions as a chaperone in the form of oligomers, and molecular chaperone activities enhanced under oxidative stress conditions. PRDX1 oligomer directly interacts with the transcription factors including c‐Myc, NF‐κB and AR, and thus affects their bioactivities upon gene regulation, which in turn induces or suppresses cell death. In addition, p53 induces the expression of apoptosis factors such as Bak and Bax under oxidative stress conditions, and promotes the activation of caspases and p53‐dependent mitochondria apoptotic signalling pathway. Importantly, PRDX1 oligomer is an essential intermediate in H₂O₂‐induced activation of c‐Abl/MST1/FOXO signalling pathway and cell apoptosis through direct interaction with p53. Furthermore, it has been recognized that c‐Abl acts as a modulator of p53. PRDX1^oli, PRDX1 oligomer.