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Review Article ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells

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Review Article ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 6175804, 17 pages https://doi.org/10.1155/2019/6175804 Review Article ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells Anastasiya V. Snezhkina , Anna V. Kudryavtseva , Olga L. Kardymon, Maria V. Savvateeva , Nataliya V. Melnikova , George S. Krasnov , and Alexey A. Dmitriev Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia Correspondence should be addressed to Anastasiya V. Snezhkina; [email protected] and Alexey A. Dmitriev; [email protected] Received 5 April 2019; Accepted 24 June 2019; Published 5 August 2019 Academic Editor: Maria Isaguliants Copyright © 2019 Anastasiya V. Snezhkina et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Reactive oxygen species (ROS) are by-products of normal cell activity. They are produced in many cellular compartments and play a major role in signaling pathways. Overproduction of ROS is associated with the development of various human diseases (including cancer, cardiovascular, neurodegenerative, and metabolic disorders), inflammation, and aging. Tumors continuously generate ROS at increased levels that have a dual role in their development. Oxidative stress can promote tumor initiation, progression, and resistance to therapy through DNA damage, leading to the accumulation of mutations and genome instability, as well as reprogramming cell metabolism and signaling. On the contrary, elevated ROS levels can induce tumor cell death. This review covers the current data on the mechanisms of ROS generation and existing antioxidant systems balancing the redox state in mammalian cells that can also be related to tumors. 1. Introduction as well as acquisition of treatment resistance [8]. On the other hand, permanent elevated ROS levels have cytotoxic effects, Reactive oxygen species (ROS) are formed as natural inducing activation of apoptotic pathways or inhibiting resis- by-products of normal cell activity and participate in cellu- tance to anticancer treatments [9]. lar signaling [1]. The increase in ROS levels has harmful In this review, we discuss the main sources of ROS pro- effects on cell homeostasis, structures, and functions and duction in animal cells and the antioxidant defense systems results in oxidative stress. As such, the disturbance of cellular that could be implicated in the redox state of cancer cells redox balance is a risk factor for the development of various (to a significant or less significant extent). pathologies [2]. Tumor cells are characterized by a high level of ROS. ROS 2. Sources of ROS Generation and Antioxidant overproduction can result from changes in many processes, Defense Systems such as oxidative phosphorylation (OXPHOS), transition metal ions, oxidase activity, protein folding, thymidine, and 2.1. Mitochondria. Mitochondria are a prime source of polyamine catabolism [3–7]. ROS can be generated both in endogenous ROS due to its main role in oxidative ATP pro- various cellular compartments and in the tumor duction, in which molecular oxygen (O ) is reduced to water 2 •− microenvironment. in the electron transport chain. The superoxide radical (O2 ) ROS have a dual role in cancer development; on one is produced at a number of sites in the mitochondria, includ- hand, they can promote molecular genetic alterations that ing complex I (sites IQ and IF), complex III (site IIIQo), glyc- are necessary for tumor initiation, growth, and progression, erol 3-phosphate dehydrogenase, Q oxidoreductase, pyruvate 2 Oxidative Medicine and Cellular Longevity dehydrogenase, and 2-oxoglutarate dehydrogenase [10]. All were also supposed to be able to generate ROS in cellular the sites release superoxide radical into the mitochondrial redox reactions [36]. The hydroxyl radicals produced can matrix (MM), and two of them, complex III (site IIIQo) attack the DNA, causing oxidative DNA adduct formation. and glycerol 3-phosphate dehydrogenase, also generate The adducts 8-hydroxy-2′-deoxyguanosine (8-OHdG) and ROS into the intermembrane mitochondrial space (IMS). 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) are the Manganese superoxide dismutase (Mn-SOD) converts the most predominant, resulting from the addition of hydroxyl superoxide radical to hydrogen peroxide (H2O2) in the radicals to guanine. These compounds are widely considered MM, while Cu- and Zn-SOD convert the superoxide radical as markers of endogenous oxidative DNA damage as well as a in the IMS or cytosol [11]. The H2O2 in the MM can further risk factor for cancer development [38]. be converted by mitochondrial aconitase to a hydroxyl • radical ( OH) via a Fenton reaction [12]. One more site of ROS production in the mitochondria is the cytochrome 2.3. Peroxisome Activity. Peroxisomes have multiple func- (CYP) catalytic cycle. CYP enzymes metabolize a wide tions in living cells, including fatty acid β-oxidation and range of organic substrates (lipids, steroid hormones, α-oxidation as well as metabolism of purines, polyamines, xenobiotics, and others) to give rise to superoxide radical amino acids, glyoxylate, reactive oxygen and nitrogen species and H2O2 as by-products [13]. Several CYP family mem- (RNS), transition metal ions, and others [39, 40]. Peroxisomes bers were shown to be present in the mitochondrial mem- generate a wide range of ROS and RNS: H O , superoxide •− • 2 2 • brane of steroidogenic organs, as well as in the liver and radical (O ), hydroxyl radical ( OH), nitric oxide (NO ), 2 − kidney [14]. Furthermore, several other mammalian pro- and peroxynitrite (ONOO ) [41]. fi teins, such as NADH-cytochrome b5 reductase [15], dihy- The peroxisome was rst described as an H2O2-produc- droorotate dehydrogenase [16, 17], complex II (succinate ing and H2O2-degrading organelle [42]. Despite the presence dehydrogenase) [18], and monoamine oxidases (MAO) of CAT, peroxisomes are one of the main sources of H2O2 [19], were shown to generate ROS in the mitochondria. [43, 44]. H2O2 is released as a by-product during the normal Mitochondria are protected from ROS by multiple catalytic activity of many peroxisomal enzymes, and it can defense systems and antioxidants: glutathione peroxidases also be generated by the spontaneous or enzymatic dismuta- (GPXs), thioredoxin peroxidases (TRXPs), superoxide dis- tion of the superoxide radical [45]. H O can generate • 2 2 mutases (SODs), peroxiredoxins (PRDXs), glutathione hydroxyl radicals ( OH) via a Fenton reaction [46]. •− (GSH), thioredoxin 2 (TRX2), glutaredoxin 2 (GRX2), Peroxisomes produce superoxide radicals (O2 ) in both cytochrome c oxidase (complex IV), coenzyme Q, ascorbic the matrix and membrane. In the matrix, two enzymes are – •− acid, tocopherol, vitamin E, and carotene [20 26]. More- responsible for O2 generation, xanthine oxidoreductase fi over, catalase (CAT), which commonly detoxi es H2O2 (XOR), and urate oxidase (UO) [47, 48]. XOR catalyzes the in the peroxisome, was found in rat heart mitochondria formation of uric acid during purine metabolism that is fur- (but not in other tissues) [27, 28]. ther converted to allantoin by UO. Both enzymes generate •− Mitochondrion-generated ROS were widely shown to O2 and H2O2. However, UO expression was not detected be implicated in various human pathologies, including in humans and some primates indicating that uric acid is a inflammation, cancer, mitochondrial and neurodegenerative terminal compound of purine metabolism [49]. The other diseases, diabetes, chronic diseases, and aging [3, 29–32]. source of superoxide radicals is an electron transport chain Elevated ROS levels and mitochondrial dysfunction, pres- in the peroxisomal membrane [50]. Moreover, XOR also cat- ent in many cancers, lead to oxidative damage of cellular alyzes the reduction of nitrates and nitrites to nitric oxide • • structures, in particular, genomic and mitochondrial (NO ) [51]. NO can also be produced from L-arginine, in DNA, somatic mutations, genome instability, activation a reaction catalyzed by nitric oxide synthase (NOS) [52]. •− • of oncogenes and inactivation of tumor suppressor genes, The reaction of O with NO results in a highly reactive 2 − and alterations in metabolic and signaling pathways with compound called peroxynitrite (ONOO ) [53]. simultaneous activation of compensatory antioxidant mech- Several antioxidant systems regulate ROS levels in perox- anisms, that all contribute to cell transformation [33]. How- isomes and defend cells from oxidative damage. These ever, overproduction of ROS can also promote tumor cell include a number of enzymes, such as CAT, superoxide dis- apoptosis and such strategies have effectively been used for mutases, peroxiredoxins, glutathione S-transferases (GST), anticancer treatment [34]. and epoxide hydrolase 2 (EPHX2), as well as nonenzymatic low-molecular weight antioxidants, which are reviewed in 2.2. Transition Metal Ions. One of the major mechanisms of detail elsewhere [39, 45, 50]. metal carcinogenicity is the ability of transition metal ions Changes in redox homeostasis contribute to cancer to induce oxidative stress [35]. Fenton and Haber-Weiss development and progression [54]. The peroxisome main- reactions are frequently responsible for ROS generation tains cellular oxidative balance, and dysregulation of its in living cells [36]. During these reactions, H2O2 is decom- activity is associated
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