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Reactive Oxygen Species: A Key Constituent in Cancer Survival

Reactive Oxygen Species: A Key Constituent in Cancer Survival 755391 BMI0010.1177/1177271918755391Biomarker InsightsKumari et al research-article2018 Biomarker Insights Reactive Oxygen Species: A Key Constituent in Cancer Volume 13: 1–9 © The Author(s) 2018 Survival Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1177271918755391 https://doi.org/10.1177/1177271918755391 Seema Kumari, Anil Kumar Badana, Murali Mohan G, Shailender G and RamaRao Malla Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India. ABSTRACT BACKg ROund: Cancer is one of the major heterogeneous disease with high morbidity and mortality with poor prognosis. Elevated levels of reactive oxygen species (ROS), alteration in redox balance, and deregulated redox signaling are common hallmarks of cancer progres- sion and resistance to treatment. Mitochondria contribute mainly in the generation of ROS during oxidative phosphorylation. Elevated levels of ROS have been detected in cancers cells due to high metabolic activity, cellular signaling, peroxisomal activity, mitochondrial dysfunc- tion, activation of oncogene, and increased enzymatic activity of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphory- lases. Cells maintain intracellular homeostasis by developing an immense antioxidant system including catalase, superoxide dismutase, and glutathione peroxidase. Besides these enzymes exist an important antioxidant glutathione and transcription factor Nrf2 which contribute in balancing oxidative stress. Reactive oxygen species–mediated signaling pathways activate pro-oncogenic signaling which eases in cancer progression, angiogenesis, and survival. Concomitantly, to maintain ROS homeostasis and evade cancer cell death, an increased level of antioxidant capacity is associated with cancer cells. COn Clu SiOn S: This review focuses the role of ROS in cancer survival pathways and importance of targeting the ROS signal involved in cancer development, which is a new strategy in cancer treatment. KeywOR d S: ROS, cancer survival, Nrf2, MMPs Re Cei Ved : July 1, 2017. ACCe PTed : December 30, 2017. de Cl ARATiOn OF COnF li CTing inT e Re STS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this Ty Pe: Review article. Funding: The author(s) disclosed receipt of the following financial support for the CORRe SPOnding Au THOR: RamaRao Malla, Cancer Biology Lab, Department of research, authorship, and/or publication of this article: The review was supported by UGC, Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam 530045, India. New Delhi, for Post-doctoral for woman (No. F.15-1/2013-14/PDFWM-2013-14-GE- Email: seemakumarisingh@gmail.com AND-12376 (SA-II). Background Cancer is one of the major heterogeneous diseases with high thiyl radicals (RS ). Other forms of ROS include singlet oxy- morbidity and mortality. Despite extensive research and con- gen () O , hydrogen peroxide (H O ), organic hydroperoxides 2 2 siderable efforts for developing targeted therapies, it is still an (ROOH), ozone/trioxygen (O ), hypochloride (HOCl), alarming condition with a poor prognosis and high mortality. nitrosoperoxycarbonate anion (O = NOOCO) , nitrocarbon- Numerous studies have provided evidence that change in redox ate anion () ON 2 OCO , peroxynitrite (ONO ), nitronium balance and deregulation of redox signaling are common hall- () NO , dinitrogen dioxide (N O ), and high-reacting lipid or 2 2 marks of cancer progression and resistance to treatment. It is carbohydrate derived including carbonyl compounds. In nor- well known that cancer cells show persistently high levels of mal cells, ROS are generated in a highly regulated manner as reactive oxygen species (ROS) due to oncogenic transforma- they are involved in the regulation of signaling processes of cell tion including alteration in genetic, metabolic, and tumor division, immune regulation, autophagy, inflammation, and microenvironment. Recent studies have demonstrated that stress-related response. However, the uncontrolled generation cancer cells are highly adapted to elevated levels of ROS by of these oxidants can lead to oxidative stress and cytotoxicity, activating antioxidant pathways. Thus, targeting the ROS imparting loss of cellular functions and development of hetero- signaling pathways and redox mechanisms involved in cancer geneous disease like cancer (Table 1). development are new potential strategies to prevent cancer. Reactive oxygen species are constantly generated during the Cellular Generation of ROS metabolic process, and their nature of existence in the form of During an aerobic cellular metabolism, ROS are constantly free radicals, ions, and molecules with a single unpaired elec- generated f rom oxygen. Mitochondria contribute the maximum tron confers them high reactivity. Broadly, ROS are grouped in the generation of ROS as it consumes approximately 80% of as oxygen-free radicals which include hydroxyl radical ( OH), molecular oxygen during oxidative phosphorylation as shown in 2 − · · · superoxide (O ), organic radicals (R ), alkoxyl radicals (RO ), Figure 1. It is well known that the electron transport chain · · nitric oxide (NO ), peroxyl radicals (ROO ), disulfides (RSSR), (ETC) encompasses 5 complexes, namely, complexes I-IV and · · thiyl peroxyl radicals (RSOO ), sulfonyl radicals (ROS ), and adenosine triphosphate (ATP) synthase on the inner membrane Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Biomarker Insights Table 1. List of free radicals and their biological damage. HALF-LIFE, S BIoL oGICAL DAMAGE REFERENCES o xyGEN-FREE RADICALS (R oS) 1. Nucleic acid mutations and Nicola et al, Geou and 3 4 strand breakage, base Peter, Levine et al, ∙ −10 Hydroxyl radical (Ho ) 10 modification Rohrmann et al, Harris and 6 7 2. Lipid peroxidation of Brugge, Griffith, Irfan and − 8 • −6 polyunsaturated fatty acids William Superoxide anion () O 10 causing chain breakage and ∙ −6 increase in membrane fluidity Alkoxyl radicals (Ro ) 10 and permeability 3. Peptide chain breakage, Peroxyl radicals (Roo ) 17 site-specific modification of amino acids, enzyme Nonradicals inactivation −6 () O 10 Singlet oxygen Hydrogen peroxide (H o ) Stable 2 2 Nitrogen-free radical (RNS) Nitric oxide (No ) s Nitrogen dioxide () NO s Nonradicals Peroxynitrite (o No ) s Dinitrogen dioxide (N o ) s 2 2 Nitrous acid (HNo ) s Figure 1. Mitochondrial generation of Ro S. The electrons generated from the metabolic intermediates lead to the production of RoS at specific location in the mitochondria (mtR oS or mR oS). The generation of the RoS mainly takes place during the process of oxidative phosphorylation at the ETC located on the inner mitochondrial membrane. Complexes I, II, and III play a pivotal role in the generation of RoS. Release of electrons at complexes I and III from electron transport chains leads to partial reduction of oxygen to form a free radical such as superoxide. Superoxide is released to the intermembrane space from complex III, owing to generation from ubisemiquinone at the outer ubiquinone-binding site (Qo) of complex III. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by 2 dismutases including superoxide dismutase 2 (SoD2). The H o is 2 2 degraded in the matrix by glutathione peroxidase (GPx). ETC indicates electron transport chain; RoS, reactive oxygen species. of mitochondria. During the process of cellular respiration, complexes I and III are released into the intermembrane space electrons are transported through a series of mitochondrial which comprises 80% of superoxide radicals generated in the complexes to the terminal electron acceptor, molecular oxygen mitochondria and remaining 20% are made by mitochondrial (O ). In the process of cellular metabolism, the electrons released matrix. The mitochondrial permeability transition pore in the from the ETC react with O to produce superoxide () O radi- outer membrane of the mitochondrion allows the passage of cals. Mitochondrial complexes I, II, and III contribute to the superoxide radicals into the cytoplasm where it is dismutated to maximum in redox signaling. Superoxide radicals generated at hydrogen peroxide, a highly diffusible secondary messenger. Kumari et al 3 This reaction is catalyzed by superoxide dismutase located in oxidative damage of the protein. This redox signaling is bal- the mitochondrial matrix (MnSOD) or in the cytosol (by Cu/ anced by peroxiredoxins and glutathione peroxidases. ZnSOD). Furthermore, aquaporin 8 serves a channel for the Reactive oxygen species can induce oxidative stress followed release of hydrogen peroxide from the cell membranes. There by altering cell membrane lipid bilayer by the process of lipid is an another major site for the generation of ROS termed as peroxidation of polyunsaturated fatty acids. This causes the peroxisomes where superoxide and H O are generated through generation of lipoperoxyl radical (LOO ), which, in turn, reacts 2 2 xanthine oxidase in the peroxisomal matrix and membranes. with a lipid to yield a lipid-based radical and a lipid hydroper- Other sources of ROS include endogenous metabolites such as oxide (LOOH). These LOOHs are unstable, and they gener- fatty acids, prostaglandins, and exogenous components includ- ate new peroxyl and alkoxy radicals and decompose to secondary ing drugs, flavorings, coloring agents, antioxidants, etc. These products. Free radicals produced during lipid peroxidation have substances are processed in the smooth endoplasmic reticulum very minute and local effects because of their short life. and transformed into f ree radicals, especially OH. Macrophages However, the breakdown products of lipid peroxides such as and leucocytes, as a part of immune response contribute to the aldehydes, malondialdehyde, hexanal, 4-hydroxynonenal 12,13 formation of free radicals. (HNE), or acrolein serves as “oxidative stress second messen- Another important signaling associated with ROS produc- gers” due to their prolonged half-life and their ability to diffuse tion is the membrane-bound enzyme NADPH oxidases f rom their site of generation. Among the products of lipid per- (NOXs). However, the NOX-mediated release of ROS, by the oxidation, HNE is chemically reactive because of its highly mechanism of the oxidative burst, is commonly associated with electrophilic nature and it easily reacts with glutathione, pro- the immune response and mediated by cells of immune system, teins, and DNA which leads to the covalent modifications on such as macrophages and neutrophils, and by inflammatory macromolecules. reactions. The NOX-mediated mechanism involves various ROS in Genomic Instability and Cancer stages such as activation of NOX genes and transmembrane Development proteins for the transport of electrons across biological mem- Cancer cells show a persistent metabolic oxidative stress com- branes where there is a reduction of molecular oxygen into pared with normal cells, which is mainly due to inherent mito- superoxide by NOX as a part of redox signaling. chondrial dysfunction and NOX activation. As a part of Oxidative Stress–Induced ROS Generation metabolic reactions, high levels of ROS are generated and Free radicals’ contribution is multifaceted in carcinogenesis and unregulated levels can lead to oxidative damage such as DNA the malignant progression of tumor cells, which may be con- mutation–causing cancer initiation and progression. These oxi- sidered as a unique characteristic of cancer. In general, low con- dative damages comprise a mixture of DNA lesions including centration of ROS acts as the mitogens and promotes cell base damage, DNA single-strand breaks, and DNA double- proliferation and survival, whereas intermediate concentration strand breaks, rearrangement of DNA sequence, base modifi- leads to a transient or permanent cell cycle arrest and induces cation, DNA miscoding lesions, gene amplification, and the cell differentiation. At high concentration, ROS can produce activation of oncogenes. oxidative damage, especially in the DNA, causing mutations Elevated levels of ROS during cancer transformation are which eventually lead to cancer. Oxidative damage caused by mainly due to high metabolic rate in mitochondrial, endoplas- ROS also contributes to alteration of proteins; one such exam- mic reticulum, and cell membranes. These changes are marked ple is the mechanism of redox signaling involving H O - by respiratory dysfunction, low coupling efficiency of the mito- 2 2 mediated oxidation of cysteine residues within proteins. chondrial ETC, raising electron leakage and increased ROS − 5 Cysteine residues exist as a thiolate anion (Cys-S ) at physio- generation. Cancer cells maintain their high energy levels logical pH and are more susceptible to oxidation compared through a high rate of glycolysis followed by lactic acid fer- with the protonated cysteine thiol (Cys-SH). During redox mentation even in the presence of abundant oxygen; this is signaling, H O oxidizes the thiolate anion to sulfenic form called aerobic glycolysis, also termed the Warburg effect, fol- 2 2 (Cys-SOH) causing allosteric changes within the protein that lowed by oxidation in mitochondria. This metabolic switch is alter its function. The sulfenic form can be reduced to thiolate essential for the cancer cells to adapt to hypoxic conditions anions by the antioxidant enzymes such as disulfide reductases, with less mitochondrial defect and ROS production. In thioredoxin (Trx), and glutaredoxin (Grx) to recover its origi- responsive to mitochondrial ROS (mROS) in cancer cells, nal state and functioning of the proteins. Hence, the oxidation hypoxia-inducible factors (HIFs) are activated to cancer cells of cysteine residues within proteins serves as a reversible signal to adapt to their diminished oxygen microenvironment which transduction mechanism when occurring at low nanomolar is essential for cell survival, growth, and proliferation. concentration of a range of H O . At higher levels of peroxide, Reactive oxygen species play a vital role at every stage of can- 2 2 the oxidized thiolate anions form sulfinic (SO H) or sulfonic cer development, including initiation, promotion, and progres- (SO H) species. Unlike sulfenic modifications, sulfinic and sul- sion. Increase in intracellular ROS levels may result in the fonic forms are irreversible which results in permanent activation of oncogenes and oncogenic signals including 4 Biomarker Insights Figure 2. Role of Ro S in signal transduction. RoS induce activation of PI3K/AKT/mT oR survival signaling leads to the activation of mainly 2 signaling pathways: Ras-MAPK, which results in cell proliferation, and PI3K-Akt-eNoS, which results in metabolic modulation and cell survival. Hypoxia causes the activation of HIFα-HIFβ, which further activates VEGF, an angiogenic growth factor. In cancer cell RoS, high concentration of R oS activates survival pathway and inactivates PTEN pathway which initiates apoptosis. R oS indicate reactive oxygen species; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor. constitutively active mutant Ras, Bcr-Abl, and c-Myc which are activated B cells (NF-κB) through polycystin-1(PKD1) to involved in cell proliferation and inactivation of tumor suppres- upregulate epidermal growth factor receptor (EGFR) pro- sor genes, angiogenesis, and mitochondrial dysfunction. High proliferative signaling. Moreover, ROS promote angiogenesis metabolism in cancer induces Wnt signal, specifically Wnt/β- and metastasis by stabilizing HIF and activating 5′-adenosine catenin pathway where c-Myc is regulated by Wnt/β-catenin monophosphate–activated protein kinase (AMPK) and one- and consequently, it can attribute greater metastatic potential. carbon metabolism pathways to enhance NADPH production and maintain redox balance. Hypoxia-induced mROS stabilize ROS as a Signaling Molecule in Cancer Sur vival the oxygen-sensitive HIF-α subunit by dimerization with HIF- H O reversibly oxidizes cysteine thiol groups of phosphatases β and induce the expression of pro-angiogenic genes. Under 2 2 such as phosphatase and tensin homolog (PTEN), protein- normoxic conditions, with sufficient oxygen, HIF-α is degraded tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2 following PHD2-mediated hydroxylation and subsequent rec- (PP2) which cause loss of their activity and promote the activa- ognition by the E3 ubiquitin ligase von Hippel-Lindau protein. tion of the PI3K/Akt/mTOR survival pathway. Moreover, To raise the antioxidant capacity and prevent ROS-mediated H O -mediated oxidation of prolyl hydroxylase domain pro- tumor cell death, AMPK is activated which promotes NADPH 2 2 tein 2 (PHD2) causes the stabilization of HIF1 during hypoxia, production and prevent anabolic processes that require NADPH which is important for cancer metastasis. The possible mech- consumption. In addition, in hypoxia, HIF-dependent upregu- anism involved in promoting targeted protein oxidation by lation of the one-carbon metabolism enzyme serine hydroxym- H O may involve the ability of ROS-scavenging enzymes ethyltransferase (SHMT2) promotes mitochondrial serine 2 2 such as glutathione peroxidase to measure and transduce the catabolism and NADPH production. H O signal which is called as redox-relay mechanism. Another It is a well-known fact that metastasis requires endothelial 2 2 mechanism proposed is called as floodgate model in which oxi- mesenchymal transition, loss of cell-cell adhesion, dissociation of dation causes inactivation of the ROS-scavenging enzymes by cancer cell f rom the primary site, and damage of basement mem- hyperoxidation or phosphorylation causing localized increases brane. Moreover, ROS have been shown to regulate numerous in H O leading to protein oxidation. signaling pathways (eg, the MAPK and PI3K/Akt pathways) 2 2 Studies have demonstrated that H O can promote the acti- and transcriptional activities (eg, HIF and Snail) to enhance 2 2 vation of Ras and growth factor signaling which in turn activates cancer cell migration and invasion. Furthermore, ROS- PI3K/Akt/mTOR, MAPK/ERK and inactivates PTEN signal- dependent oxidation of v-Src causes enhancement in the inva- ing cascades. Recently, it has been demonstrated that breast sion potential and anchorage of Src-transformed cells. Reactive cancer–associated mitochondrial DNA haplogroup promotes oxygen species has been reported to confer anoikis resistance to neoplastic growth via ROS-mediated AKT activation. Onco- cancer cells through the oxidation and activation of Src, leading genic mutations in Ras can lead to increased ROS production to constitutive, ligand-independent EGFR activation and pro- through NOX isoform (NOX4) which enhances cell prolifera- survival signaling. Elevated ROS levels resulting from mutations tion. In a recent study, it was demonstrated that Kras-derived in mitochondrial DNA, which impair the complex I activity, mROS-activated nuclear factor κ-light-chain-enhancer of have also been shown to promote the metastasis (Figure 2). Kumari et al 5 catalyzed by the malic enzyme and the isocitrate dehydroge- Cancer Progression and Effect of ROS in Metabolic nase, which eventually produces NADPH. Cancer cells use Pathways these reducing equivalents as a preventive measure against cell Recent evidence suggested that alteration and deregulation of death under loss of matrix adhesion and metabolic stress con- redox signaling are prominent hallmarks of cancer and can be ditions. Etomoxir is a drug found to impair NADPH produc- strongly compromised in malignancy and drug resistance. The tion and promote oxidative stress–induced cell death in human cancer cells exhibit persistently high levels of ROS as a conse- glioblastoma cells associated with profound ATP depletion quence of genetic, metabolic, and microenvironment-associated and to strengthen the proapoptotic effect of cytotoxic agents in instability. This high level of ROS is compensated by increased human leukemia cells. antioxidant ability by the cancer cells. Although it is contradic- Pentose phosphate pathway is a major catabolic pathway tory, this pro-oxidant shift enhances tumor growth and activates of glucose through which cancer cells produce large amounts an inflammatory response, stabilizing the HIF-14 and eventu- 27–29 of ribose 5-phosphate, a precursor of nucleotide synthesis ally reprogramming the metabolism. Due to the persistent and NADPH, and promote both ROS generation (NOXs) high ROS microenvironment, cancer cells adapt to an efficient and ROS detoxification (by replenishing the reduced GSH mechanism of ROS detoxification by showing high dependency and TRX pools). Activation of the PPP represents a key hall- on antioxidant system for their survival. Thus, different strate- mark of many cancers where this metabolic pathway is found gies have to be built up to disrupt the functional cross talk or at the crossroad between glycolytic activity, unrestricted pro- elevating the burden of oxidative stress in the presence of selec- liferation, and scavenging of excessive ROS. tive metabolic inhibitors which might induce lethality to cancer cells. Evidence suggest that cancer progression involves numer- Immune Evasion of ROS Through Antioxidant ous alterations in specific metabolic pathways involved in syn- Defense in Cancer thesis of proteins, lipids, and nucleotides. Besides this, there is Antioxidants are the first line of defense against free radicals an increase in the generation of NADPH and GSH, an antioxi- and other oxidants by either neutralizing or halting the forma- dant, and redox cofactors such as NADH and FADH. There is tion of f ree radicals. There are set of enzymes which are respon- a reciprocal cross talk between metabolism and redox balance of sible for transforming f ree radicals into stable and less damaging cancer cells, with a particular emphasis on the role of glycolysis, molecules which includes catalase (CAT), superoxide dis- glutaminolysis, fatty acid oxidation, one-carbon metabolism, 30 mutase (SOD), and glutathione peroxidase (GPx), etc. Some and the pentose phosphate pathway. of them are mentioned in the following sections. Glycolysis is an essential pathway through which glucose is transformed to pyruvate with the generation ATP and NADH. Glutathione Otto Warburg in 1924 reported that cancer cells extensively use glycolytic pathway regardless the presence of sufficient par- Glutathione has an indispensable role in maintaining intracel- tial pressure of oxygen; this phenomenon is known as the lular redox homeostasis usually during hypoxia and high pro- Warburg effect. Various studies have reported that oncogenic duction of ROS and NO . Glutathione exists in reduced activations and loss of tumor suppressor genes cause a progly- (GSH) and oxidized (glutathione disulfide, GSSG) states. In colytic shift which benefits the cancer cells to sustain growth its reduced state, it sequestrates ROS, which is transformed and and proliferation by providing macromolecules and reducing recycled by the action of the glutathione reductase enzyme equivalents, mainly pentose phosphate pathway–derived (GRd). The electron source used by this enzyme is NADPH, NADPH or glutaminolysis-derived GSH which are important which is mainly derived from the pentose phosphate pathway. to overcome oxidative stress in cancer cells. Recent studies GSH is also an essential cofactor for the enzyme GSH peroxi- showed that cancer cells in glucose deprivation increase glucose dase, which is involved in detoxification of peroxides, including metabolism to restrict the burden of ROS and prevent cell the H O generated in cell membranes that react with GSH 2 2 death. It is also noticed that inhibition of lactate dehydrogenase (Figure 3A). Peroxides have a dual role in carcinogenesis; about also impaired the cancer cell progression by decreasing the 90% of total glutathione exists in reduced form GSH and less intracellular ATP levels and inducing oxidative stress. However, than 10% in disulfide form GSSG; change in the ratio indi- inhibition of glycolysis has proven to represent a successful cates oxidative stress. strategy in selectively increasing cytotoxicity in pancreatic and breast cancer cells but not in normal cells. Nuclear factor erythroid 2–related factor 2 Fatty acid oxidation occurs in the mitochondria with the generation of NADH, FADH , and acetyl-CoA to support Nuclear factor erythroid 2–related factor 2 (Nrf2) is the basic biosynthetic pathways and produce ATP. However, in cancer region leucine-zipper transcription factor and one of the most cells, a consistent fraction of the acetyl-CoA enters into the important master regulator of antioxidant pathways. In normal tricarboxylic acid cycle and generates citrate, which is therefore conditions, Nrf2 is bound to the endogenous inhibitor Kelch- exported into the cytosol and enters into metabolic reactions like ECH-associated protein 1 (Keap1). Keap1 is a cytosolic 6 Biomarker Insights Figure 3. Immune evasion of Ro S through antioxidant defense in cancer survival. (A) H o generated in the matrix can oxidize biomolecules including 2 2 proteins, lipid membrane, and DNA-generating alkoxy radical by Fenton reaction. H o generated can be converted to Ho by catalase, glutathione 2 2 2 peroxidase. Glutathione exists in reduced form as GSH in the enzyme glutathione peroxidase and gets oxidized (GSSG) in the process of reduction of H o . o xidized glutathione (GSSG) is reduced by glutathione reductase, which obtains its equivalents NADPH from HMP shunt. (B) Nrf2-ARE pathway 2 2 activation takes place when cell is subjected to oxidative stress. In the cytoplasm, Nrf2 is constitutively bound to Keap1 form in the form of dimer—Nrf2- Keap1. During oxidative stress, Nrf2 is released from Keap1, hence allowing the transcriptional factor Nrf2 to translocate to the nucleus. Nrf2 in MAF family proteins binds with ARE-regulated genes. This activates antioxidant enzymes, pro-inflammatory response, and cell survival. ARE indicates antioxidant responsive element; HMP, hexose monophosphate; Ro S, reactive oxygen species. protein that inhibits Nrf2 signaling by promoting Nrf2 degra- including glutathione, superoxide dismutase, glutamate- dation through proteasomal pathway. When ROS react with 6-phosphate dehydrogenase, heat shock proteins and ferritin, redox reactive cysteines in Keap1, Nrf2 is released f rom Keap1, and pro- and anti-inflammatory enzymes such as cyclooxyge- hence allowing the transcriptional factor Nrf2 to translocate to nase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the nucleus. In the nucleus, Nrf2 dimerizes with basic leucine- heme oxygenase 1; it also regulates mitochondrial biogenesis. zipper partners (bZip) such as small Maf-family proteins and Some studies have proven that activation of Nrf2 may lead to binds to antioxidant responsive element (ARE), which is the inhibition of pro-inflammatory responses of Cox-2 and located in the promoter of the phase II and antioxidative genes. iNOS expression. The defense against the stress may be prob- It is a regulatory enhancer region within gene promoters. c-Jun ably due to the concentration of glutathione content and Nrf2 is then supposed to act mainly as transcriptional activator, which further provides cytoprotective effects against Fas- whereas the small Mafs as well as c-Myc inactivate gene tran- mediated apoptotic pathways. Nrf2 is inhibited by modifica- scription after Nrf2 binding. Nrf2-ARE binding regulates the tions of cysteine residues of Keap1 that apparently alter the expression genes involved in the cellular antioxidant and anti- interaction of Keap1 with Nrf2 and lead to its relocation to the inflammatory defense such as phase 2 detoxification enzymes cytoplasm where it is subsequently degraded by the ubiquitin Kumari et al 7 Figure 4. o verview of Ro S in cancer progression and specific target in cancer therapy. R o S indicate reactive oxygen species. proteasome. Therefore, Keap1 and Nrf2 act as a cellular sen- of immune regulation in cancer development. The ROS- 47–49 sor for damage caused by free oxygen radicals by the constant mediated signaling can be regulated by antioxidant defense. shuttling of Keap1 between the nucleus and the cytoplasm under normal conditions. Karyopherin-6 (KPNA6) is a pro- ROS Regulate Metastasis via Matrix tein which facilitates nuclear import and attenuates Nrf2 sign- Metalloproteinases aling, clearance of Nrf2 protein from the nucleus, and Matrix metalloproteinases (MMPs) play a pivotal role in the restoration of the Nrf2 protein to basal levels. These findings processes of cancer invasion and metastasis. Metastasis is a cas- suggest that KPNA6-mediated Keap1 nuclear import plays an cade process, including cell invasion, degradation of basement essential role in modulating the Nrf2-dependent antioxidant membranes, and stromal extracellular matrix, eventually caus- response and maintaining cellular redox homeostasis. Nrf2 ing invasion and metastasis. The MMPs are a family of related can be activated by cigarette smoke, infection, oxidative stress, enzymes that degrade extracellular matrix, which are consid- or inflammation. Impairment of Nrf2/ARE pathway leads to ered to be the important factors in facilitating tumor invasion. oxidative stress, inflammation, and mitochondrial dysfunc- It has been reported that increased expression of MMPs is pre- tion. Nrf2 is also considered as tumor suppressor because of dictive of tumor aggressiveness, metastasis, and poor patient its cytoprotective functions against oxidative stress. However, survival. Recently, MMPs have been considered to be an hyperactivation of the Nrf2 pathway creates an environment important factor in triggering epithelial-mesenchymal transi- that favors the survival of normal as well as malignant cells, tion (EMT). Expression of MMP-2, 3, 9, and 28 in EMT by protecting them against oxidative stress, chemotherapeutic the loss of intact E-cadherin increased motility and invasive- agents, and radiotherapy imparting it an oncogenic property, ness, downregulation of epithelial markers, and upregulation of and Nrf2 can be a powerful putative therapeutic target in can- mesenchymal markers. Studies demonstrated that there is an 42–45 cer treatment (Figure 3B). Carbonyl reductase 1 is another involvement of Rac signaling for cytoskeletal rearrangement important enzyme that regulates the expression of Nrf2 during and in mediating integrin signaling. Several reports have dem- oxidative stress and helps to detoxify ROS. onstrated that ROS can be generated by integrin-Rac pathway, It has been demonstrated that ROS are likely to participate resulting in tumor cell migration and invasion. 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Reactive Oxygen Species: A Key Constituent in Cancer Survival

Biomarker Insights , Volume 13 – Feb 6, 2018

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755391 BMI0010.1177/1177271918755391Biomarker InsightsKumari et al research-article2018 Biomarker Insights Reactive Oxygen Species: A Key Constituent in Cancer Volume 13: 1–9 © The Author(s) 2018 Survival Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1177271918755391 https://doi.org/10.1177/1177271918755391 Seema Kumari, Anil Kumar Badana, Murali Mohan G, Shailender G and RamaRao Malla Cancer Biology Lab, Department of Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam, India. ABSTRACT BACKg ROund: Cancer is one of the major heterogeneous disease with high morbidity and mortality with poor prognosis. Elevated levels of reactive oxygen species (ROS), alteration in redox balance, and deregulated redox signaling are common hallmarks of cancer progres- sion and resistance to treatment. Mitochondria contribute mainly in the generation of ROS during oxidative phosphorylation. Elevated levels of ROS have been detected in cancers cells due to high metabolic activity, cellular signaling, peroxisomal activity, mitochondrial dysfunc- tion, activation of oncogene, and increased enzymatic activity of oxidases, cyclooxygenases, lipoxygenases, and thymidine phosphory- lases. Cells maintain intracellular homeostasis by developing an immense antioxidant system including catalase, superoxide dismutase, and glutathione peroxidase. Besides these enzymes exist an important antioxidant glutathione and transcription factor Nrf2 which contribute in balancing oxidative stress. Reactive oxygen species–mediated signaling pathways activate pro-oncogenic signaling which eases in cancer progression, angiogenesis, and survival. Concomitantly, to maintain ROS homeostasis and evade cancer cell death, an increased level of antioxidant capacity is associated with cancer cells. COn Clu SiOn S: This review focuses the role of ROS in cancer survival pathways and importance of targeting the ROS signal involved in cancer development, which is a new strategy in cancer treatment. KeywOR d S: ROS, cancer survival, Nrf2, MMPs Re Cei Ved : July 1, 2017. ACCe PTed : December 30, 2017. de Cl ARATiOn OF COnF li CTing inT e Re STS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this Ty Pe: Review article. Funding: The author(s) disclosed receipt of the following financial support for the CORRe SPOnding Au THOR: RamaRao Malla, Cancer Biology Lab, Department of research, authorship, and/or publication of this article: The review was supported by UGC, Biochemistry, GIS, GITAM (Deemed to be University), Visakhapatnam 530045, India. New Delhi, for Post-doctoral for woman (No. F.15-1/2013-14/PDFWM-2013-14-GE- Email: seemakumarisingh@gmail.com AND-12376 (SA-II). Background Cancer is one of the major heterogeneous diseases with high thiyl radicals (RS ). Other forms of ROS include singlet oxy- morbidity and mortality. Despite extensive research and con- gen () O , hydrogen peroxide (H O ), organic hydroperoxides 2 2 siderable efforts for developing targeted therapies, it is still an (ROOH), ozone/trioxygen (O ), hypochloride (HOCl), alarming condition with a poor prognosis and high mortality. nitrosoperoxycarbonate anion (O = NOOCO) , nitrocarbon- Numerous studies have provided evidence that change in redox ate anion () ON 2 OCO , peroxynitrite (ONO ), nitronium balance and deregulation of redox signaling are common hall- () NO , dinitrogen dioxide (N O ), and high-reacting lipid or 2 2 marks of cancer progression and resistance to treatment. It is carbohydrate derived including carbonyl compounds. In nor- well known that cancer cells show persistently high levels of mal cells, ROS are generated in a highly regulated manner as reactive oxygen species (ROS) due to oncogenic transforma- they are involved in the regulation of signaling processes of cell tion including alteration in genetic, metabolic, and tumor division, immune regulation, autophagy, inflammation, and microenvironment. Recent studies have demonstrated that stress-related response. However, the uncontrolled generation cancer cells are highly adapted to elevated levels of ROS by of these oxidants can lead to oxidative stress and cytotoxicity, activating antioxidant pathways. Thus, targeting the ROS imparting loss of cellular functions and development of hetero- signaling pathways and redox mechanisms involved in cancer geneous disease like cancer (Table 1). development are new potential strategies to prevent cancer. Reactive oxygen species are constantly generated during the Cellular Generation of ROS metabolic process, and their nature of existence in the form of During an aerobic cellular metabolism, ROS are constantly free radicals, ions, and molecules with a single unpaired elec- generated f rom oxygen. Mitochondria contribute the maximum tron confers them high reactivity. Broadly, ROS are grouped in the generation of ROS as it consumes approximately 80% of as oxygen-free radicals which include hydroxyl radical ( OH), molecular oxygen during oxidative phosphorylation as shown in 2 − · · · superoxide (O ), organic radicals (R ), alkoxyl radicals (RO ), Figure 1. It is well known that the electron transport chain · · nitric oxide (NO ), peroxyl radicals (ROO ), disulfides (RSSR), (ETC) encompasses 5 complexes, namely, complexes I-IV and · · thiyl peroxyl radicals (RSOO ), sulfonyl radicals (ROS ), and adenosine triphosphate (ATP) synthase on the inner membrane Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Biomarker Insights Table 1. List of free radicals and their biological damage. HALF-LIFE, S BIoL oGICAL DAMAGE REFERENCES o xyGEN-FREE RADICALS (R oS) 1. Nucleic acid mutations and Nicola et al, Geou and 3 4 strand breakage, base Peter, Levine et al, ∙ −10 Hydroxyl radical (Ho ) 10 modification Rohrmann et al, Harris and 6 7 2. Lipid peroxidation of Brugge, Griffith, Irfan and − 8 • −6 polyunsaturated fatty acids William Superoxide anion () O 10 causing chain breakage and ∙ −6 increase in membrane fluidity Alkoxyl radicals (Ro ) 10 and permeability 3. Peptide chain breakage, Peroxyl radicals (Roo ) 17 site-specific modification of amino acids, enzyme Nonradicals inactivation −6 () O 10 Singlet oxygen Hydrogen peroxide (H o ) Stable 2 2 Nitrogen-free radical (RNS) Nitric oxide (No ) s Nitrogen dioxide () NO s Nonradicals Peroxynitrite (o No ) s Dinitrogen dioxide (N o ) s 2 2 Nitrous acid (HNo ) s Figure 1. Mitochondrial generation of Ro S. The electrons generated from the metabolic intermediates lead to the production of RoS at specific location in the mitochondria (mtR oS or mR oS). The generation of the RoS mainly takes place during the process of oxidative phosphorylation at the ETC located on the inner mitochondrial membrane. Complexes I, II, and III play a pivotal role in the generation of RoS. Release of electrons at complexes I and III from electron transport chains leads to partial reduction of oxygen to form a free radical such as superoxide. Superoxide is released to the intermembrane space from complex III, owing to generation from ubisemiquinone at the outer ubiquinone-binding site (Qo) of complex III. Subsequently, superoxide is quickly dismutated to hydrogen peroxide by 2 dismutases including superoxide dismutase 2 (SoD2). The H o is 2 2 degraded in the matrix by glutathione peroxidase (GPx). ETC indicates electron transport chain; RoS, reactive oxygen species. of mitochondria. During the process of cellular respiration, complexes I and III are released into the intermembrane space electrons are transported through a series of mitochondrial which comprises 80% of superoxide radicals generated in the complexes to the terminal electron acceptor, molecular oxygen mitochondria and remaining 20% are made by mitochondrial (O ). In the process of cellular metabolism, the electrons released matrix. The mitochondrial permeability transition pore in the from the ETC react with O to produce superoxide () O radi- outer membrane of the mitochondrion allows the passage of cals. Mitochondrial complexes I, II, and III contribute to the superoxide radicals into the cytoplasm where it is dismutated to maximum in redox signaling. Superoxide radicals generated at hydrogen peroxide, a highly diffusible secondary messenger. Kumari et al 3 This reaction is catalyzed by superoxide dismutase located in oxidative damage of the protein. This redox signaling is bal- the mitochondrial matrix (MnSOD) or in the cytosol (by Cu/ anced by peroxiredoxins and glutathione peroxidases. ZnSOD). Furthermore, aquaporin 8 serves a channel for the Reactive oxygen species can induce oxidative stress followed release of hydrogen peroxide from the cell membranes. There by altering cell membrane lipid bilayer by the process of lipid is an another major site for the generation of ROS termed as peroxidation of polyunsaturated fatty acids. This causes the peroxisomes where superoxide and H O are generated through generation of lipoperoxyl radical (LOO ), which, in turn, reacts 2 2 xanthine oxidase in the peroxisomal matrix and membranes. with a lipid to yield a lipid-based radical and a lipid hydroper- Other sources of ROS include endogenous metabolites such as oxide (LOOH). These LOOHs are unstable, and they gener- fatty acids, prostaglandins, and exogenous components includ- ate new peroxyl and alkoxy radicals and decompose to secondary ing drugs, flavorings, coloring agents, antioxidants, etc. These products. Free radicals produced during lipid peroxidation have substances are processed in the smooth endoplasmic reticulum very minute and local effects because of their short life. and transformed into f ree radicals, especially OH. Macrophages However, the breakdown products of lipid peroxides such as and leucocytes, as a part of immune response contribute to the aldehydes, malondialdehyde, hexanal, 4-hydroxynonenal 12,13 formation of free radicals. (HNE), or acrolein serves as “oxidative stress second messen- Another important signaling associated with ROS produc- gers” due to their prolonged half-life and their ability to diffuse tion is the membrane-bound enzyme NADPH oxidases f rom their site of generation. Among the products of lipid per- (NOXs). However, the NOX-mediated release of ROS, by the oxidation, HNE is chemically reactive because of its highly mechanism of the oxidative burst, is commonly associated with electrophilic nature and it easily reacts with glutathione, pro- the immune response and mediated by cells of immune system, teins, and DNA which leads to the covalent modifications on such as macrophages and neutrophils, and by inflammatory macromolecules. reactions. The NOX-mediated mechanism involves various ROS in Genomic Instability and Cancer stages such as activation of NOX genes and transmembrane Development proteins for the transport of electrons across biological mem- Cancer cells show a persistent metabolic oxidative stress com- branes where there is a reduction of molecular oxygen into pared with normal cells, which is mainly due to inherent mito- superoxide by NOX as a part of redox signaling. chondrial dysfunction and NOX activation. As a part of Oxidative Stress–Induced ROS Generation metabolic reactions, high levels of ROS are generated and Free radicals’ contribution is multifaceted in carcinogenesis and unregulated levels can lead to oxidative damage such as DNA the malignant progression of tumor cells, which may be con- mutation–causing cancer initiation and progression. These oxi- sidered as a unique characteristic of cancer. In general, low con- dative damages comprise a mixture of DNA lesions including centration of ROS acts as the mitogens and promotes cell base damage, DNA single-strand breaks, and DNA double- proliferation and survival, whereas intermediate concentration strand breaks, rearrangement of DNA sequence, base modifi- leads to a transient or permanent cell cycle arrest and induces cation, DNA miscoding lesions, gene amplification, and the cell differentiation. At high concentration, ROS can produce activation of oncogenes. oxidative damage, especially in the DNA, causing mutations Elevated levels of ROS during cancer transformation are which eventually lead to cancer. Oxidative damage caused by mainly due to high metabolic rate in mitochondrial, endoplas- ROS also contributes to alteration of proteins; one such exam- mic reticulum, and cell membranes. These changes are marked ple is the mechanism of redox signaling involving H O - by respiratory dysfunction, low coupling efficiency of the mito- 2 2 mediated oxidation of cysteine residues within proteins. chondrial ETC, raising electron leakage and increased ROS − 5 Cysteine residues exist as a thiolate anion (Cys-S ) at physio- generation. Cancer cells maintain their high energy levels logical pH and are more susceptible to oxidation compared through a high rate of glycolysis followed by lactic acid fer- with the protonated cysteine thiol (Cys-SH). During redox mentation even in the presence of abundant oxygen; this is signaling, H O oxidizes the thiolate anion to sulfenic form called aerobic glycolysis, also termed the Warburg effect, fol- 2 2 (Cys-SOH) causing allosteric changes within the protein that lowed by oxidation in mitochondria. This metabolic switch is alter its function. The sulfenic form can be reduced to thiolate essential for the cancer cells to adapt to hypoxic conditions anions by the antioxidant enzymes such as disulfide reductases, with less mitochondrial defect and ROS production. In thioredoxin (Trx), and glutaredoxin (Grx) to recover its origi- responsive to mitochondrial ROS (mROS) in cancer cells, nal state and functioning of the proteins. Hence, the oxidation hypoxia-inducible factors (HIFs) are activated to cancer cells of cysteine residues within proteins serves as a reversible signal to adapt to their diminished oxygen microenvironment which transduction mechanism when occurring at low nanomolar is essential for cell survival, growth, and proliferation. concentration of a range of H O . At higher levels of peroxide, Reactive oxygen species play a vital role at every stage of can- 2 2 the oxidized thiolate anions form sulfinic (SO H) or sulfonic cer development, including initiation, promotion, and progres- (SO H) species. Unlike sulfenic modifications, sulfinic and sul- sion. Increase in intracellular ROS levels may result in the fonic forms are irreversible which results in permanent activation of oncogenes and oncogenic signals including 4 Biomarker Insights Figure 2. Role of Ro S in signal transduction. RoS induce activation of PI3K/AKT/mT oR survival signaling leads to the activation of mainly 2 signaling pathways: Ras-MAPK, which results in cell proliferation, and PI3K-Akt-eNoS, which results in metabolic modulation and cell survival. Hypoxia causes the activation of HIFα-HIFβ, which further activates VEGF, an angiogenic growth factor. In cancer cell RoS, high concentration of R oS activates survival pathway and inactivates PTEN pathway which initiates apoptosis. R oS indicate reactive oxygen species; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor. constitutively active mutant Ras, Bcr-Abl, and c-Myc which are activated B cells (NF-κB) through polycystin-1(PKD1) to involved in cell proliferation and inactivation of tumor suppres- upregulate epidermal growth factor receptor (EGFR) pro- sor genes, angiogenesis, and mitochondrial dysfunction. High proliferative signaling. Moreover, ROS promote angiogenesis metabolism in cancer induces Wnt signal, specifically Wnt/β- and metastasis by stabilizing HIF and activating 5′-adenosine catenin pathway where c-Myc is regulated by Wnt/β-catenin monophosphate–activated protein kinase (AMPK) and one- and consequently, it can attribute greater metastatic potential. carbon metabolism pathways to enhance NADPH production and maintain redox balance. Hypoxia-induced mROS stabilize ROS as a Signaling Molecule in Cancer Sur vival the oxygen-sensitive HIF-α subunit by dimerization with HIF- H O reversibly oxidizes cysteine thiol groups of phosphatases β and induce the expression of pro-angiogenic genes. Under 2 2 such as phosphatase and tensin homolog (PTEN), protein- normoxic conditions, with sufficient oxygen, HIF-α is degraded tyrosine phosphatase 1B (PTP1B), and protein phosphatase 2 following PHD2-mediated hydroxylation and subsequent rec- (PP2) which cause loss of their activity and promote the activa- ognition by the E3 ubiquitin ligase von Hippel-Lindau protein. tion of the PI3K/Akt/mTOR survival pathway. Moreover, To raise the antioxidant capacity and prevent ROS-mediated H O -mediated oxidation of prolyl hydroxylase domain pro- tumor cell death, AMPK is activated which promotes NADPH 2 2 tein 2 (PHD2) causes the stabilization of HIF1 during hypoxia, production and prevent anabolic processes that require NADPH which is important for cancer metastasis. The possible mech- consumption. In addition, in hypoxia, HIF-dependent upregu- anism involved in promoting targeted protein oxidation by lation of the one-carbon metabolism enzyme serine hydroxym- H O may involve the ability of ROS-scavenging enzymes ethyltransferase (SHMT2) promotes mitochondrial serine 2 2 such as glutathione peroxidase to measure and transduce the catabolism and NADPH production. H O signal which is called as redox-relay mechanism. Another It is a well-known fact that metastasis requires endothelial 2 2 mechanism proposed is called as floodgate model in which oxi- mesenchymal transition, loss of cell-cell adhesion, dissociation of dation causes inactivation of the ROS-scavenging enzymes by cancer cell f rom the primary site, and damage of basement mem- hyperoxidation or phosphorylation causing localized increases brane. Moreover, ROS have been shown to regulate numerous in H O leading to protein oxidation. signaling pathways (eg, the MAPK and PI3K/Akt pathways) 2 2 Studies have demonstrated that H O can promote the acti- and transcriptional activities (eg, HIF and Snail) to enhance 2 2 vation of Ras and growth factor signaling which in turn activates cancer cell migration and invasion. Furthermore, ROS- PI3K/Akt/mTOR, MAPK/ERK and inactivates PTEN signal- dependent oxidation of v-Src causes enhancement in the inva- ing cascades. Recently, it has been demonstrated that breast sion potential and anchorage of Src-transformed cells. Reactive cancer–associated mitochondrial DNA haplogroup promotes oxygen species has been reported to confer anoikis resistance to neoplastic growth via ROS-mediated AKT activation. Onco- cancer cells through the oxidation and activation of Src, leading genic mutations in Ras can lead to increased ROS production to constitutive, ligand-independent EGFR activation and pro- through NOX isoform (NOX4) which enhances cell prolifera- survival signaling. Elevated ROS levels resulting from mutations tion. In a recent study, it was demonstrated that Kras-derived in mitochondrial DNA, which impair the complex I activity, mROS-activated nuclear factor κ-light-chain-enhancer of have also been shown to promote the metastasis (Figure 2). Kumari et al 5 catalyzed by the malic enzyme and the isocitrate dehydroge- Cancer Progression and Effect of ROS in Metabolic nase, which eventually produces NADPH. Cancer cells use Pathways these reducing equivalents as a preventive measure against cell Recent evidence suggested that alteration and deregulation of death under loss of matrix adhesion and metabolic stress con- redox signaling are prominent hallmarks of cancer and can be ditions. Etomoxir is a drug found to impair NADPH produc- strongly compromised in malignancy and drug resistance. The tion and promote oxidative stress–induced cell death in human cancer cells exhibit persistently high levels of ROS as a conse- glioblastoma cells associated with profound ATP depletion quence of genetic, metabolic, and microenvironment-associated and to strengthen the proapoptotic effect of cytotoxic agents in instability. This high level of ROS is compensated by increased human leukemia cells. antioxidant ability by the cancer cells. Although it is contradic- Pentose phosphate pathway is a major catabolic pathway tory, this pro-oxidant shift enhances tumor growth and activates of glucose through which cancer cells produce large amounts an inflammatory response, stabilizing the HIF-14 and eventu- 27–29 of ribose 5-phosphate, a precursor of nucleotide synthesis ally reprogramming the metabolism. Due to the persistent and NADPH, and promote both ROS generation (NOXs) high ROS microenvironment, cancer cells adapt to an efficient and ROS detoxification (by replenishing the reduced GSH mechanism of ROS detoxification by showing high dependency and TRX pools). Activation of the PPP represents a key hall- on antioxidant system for their survival. Thus, different strate- mark of many cancers where this metabolic pathway is found gies have to be built up to disrupt the functional cross talk or at the crossroad between glycolytic activity, unrestricted pro- elevating the burden of oxidative stress in the presence of selec- liferation, and scavenging of excessive ROS. tive metabolic inhibitors which might induce lethality to cancer cells. Evidence suggest that cancer progression involves numer- Immune Evasion of ROS Through Antioxidant ous alterations in specific metabolic pathways involved in syn- Defense in Cancer thesis of proteins, lipids, and nucleotides. Besides this, there is Antioxidants are the first line of defense against free radicals an increase in the generation of NADPH and GSH, an antioxi- and other oxidants by either neutralizing or halting the forma- dant, and redox cofactors such as NADH and FADH. There is tion of f ree radicals. There are set of enzymes which are respon- a reciprocal cross talk between metabolism and redox balance of sible for transforming f ree radicals into stable and less damaging cancer cells, with a particular emphasis on the role of glycolysis, molecules which includes catalase (CAT), superoxide dis- glutaminolysis, fatty acid oxidation, one-carbon metabolism, 30 mutase (SOD), and glutathione peroxidase (GPx), etc. Some and the pentose phosphate pathway. of them are mentioned in the following sections. Glycolysis is an essential pathway through which glucose is transformed to pyruvate with the generation ATP and NADH. Glutathione Otto Warburg in 1924 reported that cancer cells extensively use glycolytic pathway regardless the presence of sufficient par- Glutathione has an indispensable role in maintaining intracel- tial pressure of oxygen; this phenomenon is known as the lular redox homeostasis usually during hypoxia and high pro- Warburg effect. Various studies have reported that oncogenic duction of ROS and NO . Glutathione exists in reduced activations and loss of tumor suppressor genes cause a progly- (GSH) and oxidized (glutathione disulfide, GSSG) states. In colytic shift which benefits the cancer cells to sustain growth its reduced state, it sequestrates ROS, which is transformed and and proliferation by providing macromolecules and reducing recycled by the action of the glutathione reductase enzyme equivalents, mainly pentose phosphate pathway–derived (GRd). The electron source used by this enzyme is NADPH, NADPH or glutaminolysis-derived GSH which are important which is mainly derived from the pentose phosphate pathway. to overcome oxidative stress in cancer cells. Recent studies GSH is also an essential cofactor for the enzyme GSH peroxi- showed that cancer cells in glucose deprivation increase glucose dase, which is involved in detoxification of peroxides, including metabolism to restrict the burden of ROS and prevent cell the H O generated in cell membranes that react with GSH 2 2 death. It is also noticed that inhibition of lactate dehydrogenase (Figure 3A). Peroxides have a dual role in carcinogenesis; about also impaired the cancer cell progression by decreasing the 90% of total glutathione exists in reduced form GSH and less intracellular ATP levels and inducing oxidative stress. However, than 10% in disulfide form GSSG; change in the ratio indi- inhibition of glycolysis has proven to represent a successful cates oxidative stress. strategy in selectively increasing cytotoxicity in pancreatic and breast cancer cells but not in normal cells. Nuclear factor erythroid 2–related factor 2 Fatty acid oxidation occurs in the mitochondria with the generation of NADH, FADH , and acetyl-CoA to support Nuclear factor erythroid 2–related factor 2 (Nrf2) is the basic biosynthetic pathways and produce ATP. However, in cancer region leucine-zipper transcription factor and one of the most cells, a consistent fraction of the acetyl-CoA enters into the important master regulator of antioxidant pathways. In normal tricarboxylic acid cycle and generates citrate, which is therefore conditions, Nrf2 is bound to the endogenous inhibitor Kelch- exported into the cytosol and enters into metabolic reactions like ECH-associated protein 1 (Keap1). Keap1 is a cytosolic 6 Biomarker Insights Figure 3. Immune evasion of Ro S through antioxidant defense in cancer survival. (A) H o generated in the matrix can oxidize biomolecules including 2 2 proteins, lipid membrane, and DNA-generating alkoxy radical by Fenton reaction. H o generated can be converted to Ho by catalase, glutathione 2 2 2 peroxidase. Glutathione exists in reduced form as GSH in the enzyme glutathione peroxidase and gets oxidized (GSSG) in the process of reduction of H o . o xidized glutathione (GSSG) is reduced by glutathione reductase, which obtains its equivalents NADPH from HMP shunt. (B) Nrf2-ARE pathway 2 2 activation takes place when cell is subjected to oxidative stress. In the cytoplasm, Nrf2 is constitutively bound to Keap1 form in the form of dimer—Nrf2- Keap1. During oxidative stress, Nrf2 is released from Keap1, hence allowing the transcriptional factor Nrf2 to translocate to the nucleus. Nrf2 in MAF family proteins binds with ARE-regulated genes. This activates antioxidant enzymes, pro-inflammatory response, and cell survival. ARE indicates antioxidant responsive element; HMP, hexose monophosphate; Ro S, reactive oxygen species. protein that inhibits Nrf2 signaling by promoting Nrf2 degra- including glutathione, superoxide dismutase, glutamate- dation through proteasomal pathway. When ROS react with 6-phosphate dehydrogenase, heat shock proteins and ferritin, redox reactive cysteines in Keap1, Nrf2 is released f rom Keap1, and pro- and anti-inflammatory enzymes such as cyclooxyge- hence allowing the transcriptional factor Nrf2 to translocate to nase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the nucleus. In the nucleus, Nrf2 dimerizes with basic leucine- heme oxygenase 1; it also regulates mitochondrial biogenesis. zipper partners (bZip) such as small Maf-family proteins and Some studies have proven that activation of Nrf2 may lead to binds to antioxidant responsive element (ARE), which is the inhibition of pro-inflammatory responses of Cox-2 and located in the promoter of the phase II and antioxidative genes. iNOS expression. The defense against the stress may be prob- It is a regulatory enhancer region within gene promoters. c-Jun ably due to the concentration of glutathione content and Nrf2 is then supposed to act mainly as transcriptional activator, which further provides cytoprotective effects against Fas- whereas the small Mafs as well as c-Myc inactivate gene tran- mediated apoptotic pathways. Nrf2 is inhibited by modifica- scription after Nrf2 binding. Nrf2-ARE binding regulates the tions of cysteine residues of Keap1 that apparently alter the expression genes involved in the cellular antioxidant and anti- interaction of Keap1 with Nrf2 and lead to its relocation to the inflammatory defense such as phase 2 detoxification enzymes cytoplasm where it is subsequently degraded by the ubiquitin Kumari et al 7 Figure 4. o verview of Ro S in cancer progression and specific target in cancer therapy. R o S indicate reactive oxygen species. proteasome. Therefore, Keap1 and Nrf2 act as a cellular sen- of immune regulation in cancer development. The ROS- 47–49 sor for damage caused by free oxygen radicals by the constant mediated signaling can be regulated by antioxidant defense. shuttling of Keap1 between the nucleus and the cytoplasm under normal conditions. Karyopherin-6 (KPNA6) is a pro- ROS Regulate Metastasis via Matrix tein which facilitates nuclear import and attenuates Nrf2 sign- Metalloproteinases aling, clearance of Nrf2 protein from the nucleus, and Matrix metalloproteinases (MMPs) play a pivotal role in the restoration of the Nrf2 protein to basal levels. These findings processes of cancer invasion and metastasis. Metastasis is a cas- suggest that KPNA6-mediated Keap1 nuclear import plays an cade process, including cell invasion, degradation of basement essential role in modulating the Nrf2-dependent antioxidant membranes, and stromal extracellular matrix, eventually caus- response and maintaining cellular redox homeostasis. Nrf2 ing invasion and metastasis. The MMPs are a family of related can be activated by cigarette smoke, infection, oxidative stress, enzymes that degrade extracellular matrix, which are consid- or inflammation. Impairment of Nrf2/ARE pathway leads to ered to be the important factors in facilitating tumor invasion. oxidative stress, inflammation, and mitochondrial dysfunc- It has been reported that increased expression of MMPs is pre- tion. Nrf2 is also considered as tumor suppressor because of dictive of tumor aggressiveness, metastasis, and poor patient its cytoprotective functions against oxidative stress. However, survival. Recently, MMPs have been considered to be an hyperactivation of the Nrf2 pathway creates an environment important factor in triggering epithelial-mesenchymal transi- that favors the survival of normal as well as malignant cells, tion (EMT). Expression of MMP-2, 3, 9, and 28 in EMT by protecting them against oxidative stress, chemotherapeutic the loss of intact E-cadherin increased motility and invasive- agents, and radiotherapy imparting it an oncogenic property, ness, downregulation of epithelial markers, and upregulation of and Nrf2 can be a powerful putative therapeutic target in can- mesenchymal markers. Studies demonstrated that there is an 42–45 cer treatment (Figure 3B). Carbonyl reductase 1 is another involvement of Rac signaling for cytoskeletal rearrangement important enzyme that regulates the expression of Nrf2 during and in mediating integrin signaling. Several reports have dem- oxidative stress and helps to detoxify ROS. onstrated that ROS can be generated by integrin-Rac pathway, It has been demonstrated that ROS are likely to participate resulting in tumor cell migration and invasion. MMP-3– as immunosuppressive agents in cancer microenvironment and induced EMT appears to be mediated via induction of ROS facilitate tumor invasion, metastasis, and resistance. Studies and increased expression of the Rac1b. The ROS-quenching have demonstrated that ROS play a crucial role in inhibitory agent N-acetyl cysteine (NAC) effectively inhibited the MMP- activities of tumor-induced immunosuppressive cells. Therefore, 3–induced EMT. These results clearly suggest that the treat- ROS are not only mediators of oxidative stress but also players ment with MMP-3 stimulates the expression of Rac1b, which 8 Biomarker Insights 14. Arvind P, Malaya KS, Diana O, Sanjay B. NADPH oxidases: an overview from increases intracellular ROS, leading to the induction of EMT, structure to innate immunity-associated pathologies. Cell Molec Immunol. suggesting that MMP-3 inhibitor or the inhibitors of ROS 2015;12:5–23. 15. del Rio LA. 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Published: Feb 6, 2018

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