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      The role of peroxiredoxins in cancer

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          Abstract

          Peroxiredoxins (PRDXs) are a ubiquitously expressed family of small (22–27 kDa) non-seleno peroxidases that catalyze the peroxide reduction of H 2O 2, organic hydroperoxides and peroxynitrite. They are highly involved in the control of various physiological functions, including cell growth, differentiation, apoptosis, embryonic development, lipid metabolism, the immune response, as well as cellular homeostasis. Although the protective role of PRDXs in cardiovascular and neurological diseases is well established, their role in cancer remains controversial. Increasing evidence suggests the involvement of PRDXs in carcinogenesis and in the development of drug resistance. Numerous types of cancer cells, in fact, are characterized by an increase in reactive oxygen species (ROS) production, and often exhibit an altered redox environment compared with normal cells. The present review focuses on the complex association between oxidant balance and cancer, and it provides a brief account of the involvement of PRDXs in tumorigenesis and in the development of chemoresistance.

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          The role of antioxidants in the chemistry of oxidative stress: A review.

          Aurelia Pisoschi, Aneta Pop (2015)
          This Review Article is focused on the action of the reactive oxygenated species in inducing oxidative injury of the lipid membrane components, as well as on the ability of antioxidants (of different structures and sources, and following different mechanisms of action) in fighting against oxidative stress. Oxidative stress is defined as an excessive production of reactive oxygenated species that cannot be counteracted by the action of antioxidants, but also as a perturbation of cell redox balance. Reactive oxygenated/nitrogenated species are represented by superoxide anion radical, hydroxyl, alkoxyl and lipid peroxyl radicals, nitric oxide and peroxynitrite. Oxidative stress determines structure modifications and function modulation in nucleic acids, lipids and proteins. Oxidative degradation of lipids yields malondialdehyde and 4-hydroxynonenal, but also isoprostanes, from unsaturated fatty acids. Protein damage may occur with thiol oxidation, carbonylation, side-chain oxidation, fragmentation, unfolding and misfolding, resulting activity loss. 8-hydroxydeoxyguanosine is an index of DNA damage. The involvement of the reactive oxygenated/nitrogenated species in disease occurrence is described. The unbalance between the oxidant species and the antioxidant defense system may trigger specific factors responsible for oxidative damage in the cell: over-expression of oncogene genes, generation of mutagen compounds, promotion of atherogenic activity, senile plaque occurrence or inflammation. This leads to cancer, neurodegeneration, cardiovascular diseases, diabetes, kidney diseases. The concept of antioxidant is defined, along with a discussion of the existent classification criteria: enzymatic and non-enzymatic, preventative or repair-systems, endogenous and exogenous, primary and secondary, hydrosoluble and liposoluble, natural or synthetic. Primary antioxidants are mainly chain breakers, able to scavenge radical species by hydrogen donation. Secondary antioxidants are singlet oxygen quenchers, peroxide decomposers, metal chelators, oxidative enzyme inhibitors or UV radiation absorbers. The specific mechanism of action of the most important representatives of each antioxidant class (endogenous and exogenous) in preventing or inhibiting particular factors leading to oxidative injury in the cell, is then reviewed. Mutual influences, including synergistic effects are presented and discussed. Prooxidative influences likely to occur, as for instance in the presence of transition metal ions, are also reminded.
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            Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

            Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto (2011)
            The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
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              Peroxiredoxins are conserved markers of circadian rhythms

              Rachel Edgar, Edward W Green, Yuwei Zhao … (2012)
              Summary Cellular life emerged ~3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles due to the Earth’s rotation. The advantage conferred upon organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation-reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterising their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription-translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular time-keeping with redox homeostatic mechanisms following the Great Oxidation Event ~2.5 billion years ago.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Clin Oncol
                Journal ID (iso-abbrev): Mol Clin Oncol
                Journal ID (publisher-id): MCO
                Title: Molecular and Clinical Oncology
                Publisher: D.A. Spandidos
                ISSN (Print): 2049-9450
                ISSN (Electronic): 2049-9469
                Publication date (Print): February 2017
                Publication date (Electronic): 10 January 2017
                Publication date PMC-release: 10 January 2017
                Volume: 6
                Issue: 2
                Pages: 139-153
                Affiliations
                [1 ]Department of Experimental Medicine, Sapienza University of Rome, I-00161 Rome, Italy
                [2 ]Department of Molecular Medicine, Sapienza University of Rome, I-00161 Rome, Italy
                Author notes
                Correspondence to: Professor Anna Coppa, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, I-00161 Rome, Italy, E-mail: anna.coppa@ 123456uniroma1.it
                Article
                Publisher ID: MCO-0-0-1129
                DOI: 10.3892/mco.2017.1129
                PMC ID: 5351761
                PubMed ID: 28357082
                SO-VID: b32c5513-11d8-4401-9758-73aa481252e5
                Copyright © Copyright: © Nicolussi et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 01 July 2016
                Date accepted : 17 November 2016
                Categories
                Subject: Review

                Keywords: peroxiredoxins,oxidative stress,tumorigenesis,chemoresistance,chemosensitization
                Data availability:
                Keywords: peroxiredoxins, oxidative stress, tumorigenesis, chemoresistance, chemosensitization

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