Oxidative stress in carcinogenesis

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Current Opinion in

Toxicology

Oxidative stress in carcinogenesis James E. Klaunig and Zemin Wang Abstract

Carcinogenesis is a multistep process involving both mutation of critical genes and increased cell proliferation. Over production of oxygen species (ROS) occurs from endogenous and/or exogenous sources. Endogenous sources include both intracellular organelles as well as inflammatory sources. Exogenous sources include xenobiotics, pharmaceuticals and radiation. Important to carcinogenesis, the resulting oxidative stress can induce mutations in critical cellular genes under inhibited antioxidant defense pathways and DNA repair mechanisms. In addition, ROS can activate a number of signal transduction pathways such as HIF1a, Nrf2, AP-1, and NF-kB that transcript cell growth regulatory genes. It is clear that oxidative stress and damage participate in all stages of the cancer process. Oxidative stress has also been linked to a number of human cancers both as causing and modulating factor. Further, the susceptibility to human cancers can be modified by polymorphisms in oxidative DNA repair genes and antioxidant genes. Addresses Indiana University, Bloomington, IN 47405, USA Corresponding author: Klaunig, James E, Environmental Health Department, Indiana University, Bloomington, IN, 47408, USA. ([email protected])

Current Opinion in Toxicology 2018, 7:116–121 This review comes from a themed issue on Oxidative Toxicology: Role of ROS Available online 1 December 2017 For a complete overview see the Issue and the Editorial https://doi.org/10.1016/j.cotox.2017.11.014 2468-2020/© 2017 Published by Elsevier B.V.

Keywords Oxidative stress, ROS, Multistage carcinogenesis, DNA damage, Proliferation, Polymorphism.

1. Introduction The formation of a neoplasia is a multistep process. In its basic form this process involves genetic modification of genomic DNA (formation of a mutated cell) followed by the selective growth of the mutated cell. This growth can be stimulated by either an increase in the cell division rate of the mutated cell and/or a decrease in the death rate (apoptosis) of the mutated cell. As the mutated cell further divides, additional epigenetic and genetic changes occur in the newly formed lesion. Previous investigations characterized the changes that occur in tumorigenesis leading to the designations of initiation, promotion and progression to describe cellular Current Opinion in Toxicology 2018, 7:116–121

and pathological demonstrable stages [1]. Initiation involves the formation of a mutated, preneoplastic cell from a genotoxic event. The formation of the preneoplastic, initiated cell is an irreversible, but dosedependent process. Promotion involves the selective clonal expansion of the initiated cell through an increase in cell growth through either an increase in cell proliferation and/or a decrease in apoptosis in the target cell population [2]. The events of this stage are dose dependent and reversible upon removal of the tumor promotion stimulus. Progression, the third stage, involves cellular and molecular changes that occur from the preneoplastic to the neoplastic state. This stage is irreversible, involves genetic instability, changes in nuclear ploidy, and disruption of chromosome integrity. Subsequent investigations have shown that carcinogenesis is much more complicated, however utilization of the three-stage process is useful in understating where and how modifiers of the cancer process function. Based on our knowledge of multistage carcinogenesis. It is apparent that chemicals that induce cancer can function at all stages of the process (complete carcinogens) or at selective stages (initiation stage (tumor initiators)) and the promotion stage (tumor promoters) [3] (Fig. 1). Using the rodent liver model as an example, the mechanisms of action by which carcinogens induce hepatic cancer can be categorized based upon molecular targets and cellular effects that include genotoxic (DNA reactive) and nongenotoxic (epigenetic) mechanisms [3]. Genotoxic agents usually refer to chemicals that directly damage genomic DNA, which in turn can result in mutation and/or clastogenic changes. Chemicals in this category are frequently activated in the target cell and produce a dose-dependent increase in neoplasm formation. A second category of carcinogenic compounds (nongenotoxic) appear to function through nonDNA reactive or indirect DNA reactive mechanisms. Nongenotoxic carcinogens, they modulate cell growth and cell death. Changes in gene expression and cell growth parameters are paramount in the action of nongenotoxic carcinogens. These agents frequently function during the promotion stage of the cancer process [4,5]. Increased replicative DNA synthesis and subsequent cell division is important in each of the stages of carcinogenesis [4,6]. Two possible mechanisms have been proposed for the induction of cancer by nongenotoxic agents. In one, an increase in DNA synthesis and cell proliferation by a nongenotoxic carcinogens may induce mutations in dividing cells through misrepair. With continual cell division, mutations will www.sciencedirect.com

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Fig. 1

Role of Oxidative Stress and Damage in Multistate Carcinogenesis. Diagram showing the multistage process of carcinogenesis using the three general stage designations. Oxidative stress and resulting oxidative damage can occur at multiple steps of the cancer process from the formation of the mutated cell (initiation) to the promotion of the mutated cell (cell proliferation; epigenetic effects) and eventual formation of the neoplasm (progression).

result in an initiated preneoplastic cell that may clonally expand to a neoplasm. In addition, nongenotoxic agents may serve to stimulate the selective clonal growth of already “spontaneously initiated cells [7]. A number of studies have shown an important role for reactive oxygen species (ROS) in tumor development [8]. ROS can be produced from endogenous sources (mitochondria, peroxisomes, and inflammatory cell activation) [9] as well as exogenous sources (environmental agents, radiation, pharmaceuticals, and industrial chemicals) (Fig. 2). Oxidative stress may in turn lead to genetic mutation and/or alterations in cell growth. A linkage between an increase in reactive oxygen radicals and cancer formation has been established. During neoplasm formation, reactive oxidants can be generated from both endogenous and exogenous sources. In addition, chemical carcinogens have been shown to override of the cellular antioxidant systems and/or the DNA repair systems Endogenous sources of reactive oxidant species include both intracellular (peroxisomes, mitochondria, and cytochrome P450) and extracellular (inflammatory cells). Exogenous sources of reactive oxygen include radiation, metals, pathogens, chemotherapeutic agents and other xenobiotic chemicals. Both endogenous and exogenous sources of ROS can interact and modify all stages of the cancer process (Fig. 1).

2. Oxidative DNA damage Oxidative DNA damage is a major source of mutations. Estimates of 10,000 (human) to 100,000 (mouse) oxidative lesions are formed per day in normal cells [10e 12], with an estimated frequency of resulting oxidative DNA damage in human cells to be 104 lesions/cell/day [13]. Being highly reactive, the hydroxyl radical is the predominant ROS that targets DNA [13]. Cell death, www.sciencedirect.com

DNA mutation, replication errors, and genomic instability can occur if the oxidative DNA damage is not repaired prior to DNA replication [9,14]. The most extensively studied and most abundant oxidative DNA lesion produced is 8-hydroxydeoxy guanosine (8OHdG), which is mutagenic in bacterial and mammalian cells [15]. While most of the oxidative DNA lesions are in the form of OH8dG, additional oxidative DNA adducts have been identified [16,17]. 8-OHdG levels are elevated in various human cancers [18e20] and in animal models of tumors [21]. Central to the induction of cancer is the production of unrepairable DNA damage in the target cell that, after a round of DNA replication, results in a mutated cell. Reactive oxygen species are able to induce both singleor double-stranded DNA breaks, DNA cross links and base modification. While several can form oxidized bases, the hydroxyl radical has been studied extensively for its oxidized DNA lesions [22]. Oxidation of guanine at the C8 position results in the formation of 8hydroxydeoxyguanosine (OH8dG), probably the most studied oxidative DNA adduct. The OH8dG DNA lesion results in site-specific mutagenesis in bacterial and mammalian cells. OH8dG also produces doserelated increases in cellular transformation [23]. Reactive oxygen species can also interact with the nucleotide pool, specifically dGTP to produce OH8dG. OH8dG in the nucleotide pool can therefore be incorporated into DNA during replication resulting in A:T to C:G transversions [15,17]. Besides OH8dG, other oxidative DNA lesions and uracil analogs have been shown to be mutagenic [24,25]. In addition to reactive oxygen species, reactive nitrogen species, such as peroxynitrites and nitrogen oxides, have also been implicated in carcinogenesis [26]. Peroxynitrite has been shown to react with guanine producing a 8-nitroguanine adduct Current Opinion in Toxicology 2018, 7:116–121

Author's Personal Copy 118 Oxidative Toxicology: Role of ROS

Fig. 2

Sources of Oxidative Stress and Effects on Carcinogenesis Endpoints. Diagram showing the influence of endogenous and exogenous sources of oxidative stress on carcinogenesis endpoints. Genetic (SNPs) and non-genetic repair pathways can be overrun by excess oxidative stress resulting in ROS that can in turn damage DNA or alter gene expression (in particular cell growth genes) resulting in activity on the carcinogenesis process.

that can induce G:C/T:A transversions [27]. As noted above, ROS can arise through a variety of events and pathways. Thus, oxidized DNA bases are capable of inducing mutations that are commonly observed in neoplasia functioning at the initiation stage of the cancer process.

enzymes. High levels of ROS may result in apoptosis or necrosis while lower levels produce altered expression of growth factors and proto oncogenes [29] leading to increases in cell proliferation. ROS-induced alteration of gene expression occurs through modulation of several signaling pathways.

3. Modulation of gene expression

ROS can activate kinases, including protein kinase C (PKC) which regulate cell cycle modification [30]. This pathway regulates cell proliferation and survival linking its activation to ROS-induced carcinogenesis. Activation of transcription factors on signaling pathways has also been reported following ROS exposure. In particular,

Besides the effects of ROS on DNA damage, the role of ROS on epigenetic or nongenotoxic effects has been investigated [28]. Exposure to ROS inducing agents results in the upregulation of stress response genes, including those involved in antioxidant defense Current Opinion in Toxicology 2018, 7:116–121

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Fig. 3

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intimately involved in the maintenance of concerted networks of gene expression that underlie neoplastic development.

4. Endogenous sources of ROS

Role of Level of Oxidative Stress on the Cellular Response in Carcinogenesis. Diagram displaying the role of dose response of level of oxidative stress on the response of the cell with particular interest in the carcinogenesis stages (see Fig. 1). High dose oxidative stress result in cell death (necrosis or apoptosis). Since tumors in general are more resistant to cell death by oxidative stress, high ROS doses may allow for selective growth of the tumors (tumor promotion). Medium doses of ROS may induce DNA damage and mutation resulting in the formation of an initiated cell (tumor initiation). Lower doses of ROS will influence gene expression and particular those genes responsible for the cell growth of mutated cells (tumor promotion).

Nrf2, NF-kB, AP-1 and HIF-1a are targeted by ROS [31e 33]. The activation of these transcription factors is ROS dose dependent and thus depending on level of ROS leads to cell death or cell proliferation (Fig. 3). Both endogenous and exogenous stressors have been reported to activate Nrf2 (e.g., ROS, RNS) [34]. The activation of Nrf2 results in a broad spectrum of protective enzymes including those involved in xenobiotic detoxification, antioxidative response, and proteome maintenance [31]. Low levels of Nrf2 or complete loss of Nrf2 activity appears to increase ROS production and DNA damage and predisposes cells to tumorigenesis. AP-1 was first identified as a transcription factor that contributes both to basal gene expression [35]. AP-1 activity can be induced by H2O2 and is also regulated by the redox state of cysteine in the cell [36]. AP-1 activation produces increased cell proliferation as a result of increased expression of growth-stimulatory genes [37]. NF-kB is a nuclear transcription factor involved in cell survival, differentiation, inflammation, and growth [38]. NF-kB is also a direct target for ROS, which can affect the ability of NF-kB to bind to DNA [32]. Activation of transcription factors is clearly stimulated by activation of ROS-mediated signal transduction pathways. Through their ability to stimulate cell growth through regulation of apoptosis and/or cell division, transcription factors can mediate many of the physiological and pathological effects of exposure ROS. Through regulation of gene transcription factors, and disruption of signal transduction pathways, ROS is www.sciencedirect.com

Potential endogenous sources of ROS include mitochondria oxidative phosphorylation, P450 metabolism, peroxisomes, and inflammatory cell activation (Fig. 2). With mitochondrial oxidative metabolism, approximately 4%e5% of molecular oxygen is converted to ROS (primarily superoxide). Superoxide can be dismutated by superoxide dismutase to yield hydrogen peroxide which can subsequently be converted to a hydroxyl radical [39]. Recent studies have examined a link between mitochondrial-induced ROS and tumor development [8,40]. ROS generated from mitochondria is higher in cancer cells than normal cells [41]. Inflammatory cells, including neutrophils, eosinophils, and macrophages also are an endogenous source reactive oxygen species. Activated macrophages produce a variety of reactive oxygen species, including superoxide anion, hydrogen peroxide, and nitric oxide. Peroxisomes are organelles that consume oxygen and also contribute to cellular ROS generation. The production of ROS in the peroxisome involves acyl-CoA oxidase and xanthine oxidase, which generate hydrogen peroxide and superoxide anions [42]. In rat liver, peroxisomes account for 35% of all H2O2 produced from normal oxygen consumption [42]. Compounds that increase peroxisome number (and amount of H2O2 produced) such as hypolipidemic drugs, phthalate esters, and halogenated solvents all produce tumors in the liver [43,44], suggesting a causal link between peroxisome proliferation-induced ROS and liver tumorigenesis [45,46].

5. Exogenous sources of ROS A number of physical and chemical agents that induce cancer in mammalian species have been implicated as functioning through oxidative stress mediated processes. Ionizing radiation is an established carcinogen that functions at all stages of the carcinogenesis process [47]. Ionizing radiation effects are mediated through ROS from the radiolysis of water resulting in DNA damage leading to gene mutation and cancer [48]. Environmental agents including non-DNA reactive carcinogens (nongenotoxic) can generate ROS directly through metabolized intermediates or through activation of endogenous sources of ROS [49]. The induction of oxidative stress and damage has been observed following exposure to xenobiotics of varied structures and activities. Chlorinated compounds, radiation, metal ions, barbiturates, phorbol esters, and some peroxisomeproliferating compounds are among the classes of compounds that induce oxidative stress and cancer [49]. Therapeutic agents, in particular antineoplastic drugs are another exogenous source of ROS. Cisplatin and Current Opinion in Toxicology 2018, 7:116–121

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adriamycin for example produce high levels of ROS resulting in extensive DNA damage and cell death.

7.

Ames BN, Gold LS: Too many rodent carcinogens: mitogenesis increases mutagenesis. Science 1990, 249(4972): 970–971.

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Ishikawa K, et al.: ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 2008, 320(5876):661–664.

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Klaunig JE, Kamendulis LM: The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004, 44: 239–267.

6. Polymorphisms in oxidative stress Single nucleotide polymorphisms (SNPs) constitute the majority of genetic variation observed in the human population [50]. Genetic polymorphisms in oxidative stress-related genes have been investigated with regard to cancer susceptibility. SNPs of interest are involved in pathways in carcinogen metabolism (detoxification and/ or activation), antioxidants, and DNA repair pathways. The metabolism of carcinogens, both genotoxic and nongenotoxic, involves both phase I (activation) and phase II (detoxification) reactions. Phase I reactions are mediated by cytochrome P450 (CYP) gene super families that responsible for the metabolism of endogenous and exogenous compounds including drugs and xenobiotics [51]. Cytochrome pathways utilize oxygen in producing their products and have the ability to form ROS during induction. Phase II enzymes include Glutathione S-transferases (GSTs), a superfamily of phase II enzymes that catalyze the conjugation of electrophilic molecules with glutathione and thereby protect cellular macromolecules against oxidative stress [52]. Antioxidant enzymes including superoxide dismutase (CuZnSOD and MnSOD), glutathione peroxidases (GPX) and Catalase (CAT) have SNPs that have been linked to increased incidence and susceptibility to cancer [53]. Polymorphisms have also been described in DNA repair genes. 8-OHdG DNA lesions are preferentially repaired by base excision repair (BER) enzymes, including 8-oxo-guanine DNA glycosylase (OGG1), apurinic/apyrimidinic (AP) and endonuclease 1 (APE1). Several SNPs within hOGG1 have been reported [54]. Polymorphisms of OGG1 alter glycosylase function and the ability to repair oxidative DNA damage. Epidemiologic studies investigating the association between the SNPs of OGG1 have been linked to increase in human cancers [55e57]. Polymorphisms in APE1 have been reported and linked to increased cancer risk [58].

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