Regulation of catalase expression in healthy and cancerous cells
Graphical abstract
Introduction
The human catalase gene is located on the short arm of chromosome 11 [1] and has all the characteristics of a housekeeping gene, with no TATA box, no initiator element sequence, and high GC content in the promoter [2]. The complete genomic DNA coding sequence for catalase has 32,420 bp and contains 12 introns and 13 exons, generating an mRNA of 2287 bp [2] encoding a single protein of 526 amino acids. The enzyme (EC 1.11.1.6), first described by Loew more than 100 years ago [3], is a homotetramer in which each monomer (62.5 kDa) contains a heme b group responsible for the enzymatic activity [4]. The human catalase belongs to the family of typical catalases [5], which predominantly catalyze the dismutation of hydrogen peroxide (H2O2) into water and molecular oxygen. In addition to its dominant “catalatic” activity (decomposition of H2O2), catalase can also decompose peroxynitrite [6], [7], [8], oxidize nitric oxide to nitrogen dioxide [9], and exhibit marginal peroxidase (i.e., oxidation of organic substrates with concomitant reduction of a peroxide ) [10] as well as low oxidase activity (O2-dependent oxidation of organic substrates) [11].
In metazoans, catalase is expressed in all major body organs, especially in the liver, kidney, and erythrocytes [12], [13], where it plays an essential role in cell defense against oxidative stress [14]. The enzyme is mainly located in peroxisomes [15], [16], but a functional catalase has also been detected in the cytoplasm [17], [18], in the mitochondria of rat cardiomyocytes [19], and on the cytoplasmic membrane of human cancer cells [20].
Altered catalase expression has been associated with several diseases. For example, certain polymorphisms in the catalase gene have been described in diabetes, hypertension, vitiligo, Alzheimer disease, and acatalasemia, leading to decreased catalase activities [21], [22].
Catalase is frequently downregulated in human and rodent tumor tissues compared to normal tissues of the same origin [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. The low levels of catalase expression correlate with a high production of H2O2, which is involved in the activation of signaling pathways to induce proliferation, migration, and invasion in cancer cells [36], [37], [38]. We have previously reported an important decrease in catalase activity in both human and murine cancer cells [39], [40]. These observations are consistent with a study by Sun et al., who showed that immortalization and transformation of mouse liver cells with SV40 (simian virus 40) resulted in a decrease in catalase expression that contributed to oncogenesis by increasing reactive oxygen species (ROS) levels in transformed cells [41].
Conversely, catalase levels increase in rat hepatocytes and astrocytes as well as in Chinese hamster V79 fibroblasts after short-duration exposure to H2O2 [42], [43], [44]. However, short-term exposures to oxidants (i.e., hydrogen peroxide, menadione, tert-butyl hydroperoxide) fail to induce catalase protein levels in MCF-7 breast cancer cells, MRC-9 normal lung fibroblasts, or PC12 rat pheochromocytoma cells [45], [46], [47]. The expression of other H2O2-degrading enzymes (i.e., glutathione peroxidase) is induced and may counteract the increased ROS level in MCF-7 after exposure to oxidants [45]. It is noticed that the change in catalase expression, after short-term H2O2 exposure, would be influenced by several factors: the exposure time, the H2O2 concentration, the basal antioxidant enzyme capacity of the cells, and the cellular model used.
Moreover, in patients suffering from mesothelioma and in rat glioma cells, catalase protein levels are increased, conferring cellular protection against epirubicin and ionizing radiation (137Cs γ-rays), respectively [48], [49]. Increased catalase expression has been observed in tumors from patients with gastric carcinoma, skin cancer, and chronic myeloid leukemia [50], [51], [52], [53] and in human HL-60 cancer cells rendered resistant to chronic exposure to H2O2 [54], [55], [56]. This high catalase expression has also been observed in several human cancer cell lines (e.g., gastric, oral, pancreatic, bladder) exposed to cisplatin [57], ascorbic acid [58], bleomycin [59], gemcitabine [60], mitomycin C [61], hormonal therapy [62], and ionizing radiation [63].
The importance of catalase for human life is illustrated by the diseases that are associated with mutations of its gene. For example, acatalasemia is an autosomally inherited deficiency of erythrocyte catalase due to guanine-to-adenine substitution (Japanese type A), threonine deletion (Japanese type B), or guanine–adenine insertion (Hungarian type) [64], [65], [66]. Acatalasemia is characterized by a specific catalatic activity of less than 5% compared to normal rates; it is still rare and usually benign but can sometimes be problematic, resulting in oral gangrene ulceration for Japanese patients or in essential hypertension [67], [68], [69]. Catalase polymorphism has also been associated with the occurrence of diabetes, vitiligo, or Alzheimer disease [21], [22]. Regarding catalase downregulation, it should be noted that catalase-deficient mice are viable and fertile [70]. They develop normally with a normal hematological profile, but after trauma the mitochondria show defects in oxidative phosphorylation. This phenotype could be explained by the presence of other H2O2-degrading enzymes such as glutathione peroxidases and peroxiredoxins. On the other hand, the enzyme was also overexpressed in mice. Mitochondrial catalase overexpression in mice enables a life-span increase of 20% [71]. In these mice, the mitochondrial deletions are reduced; they prevent heart disease and the onset of cataracts.
As previously cited, the first function assigned to catalase is the transformation of hydrogen peroxide into oxygen and water (2 H2O2 → 2 H2O + O2). It thus plays an important role in defending cells against oxidative damage by degrading hydrogen peroxide. However, increasing evidence suggests that catalase is also involved in various other processes.
Indeed, ROS are able to activate various signaling pathways, such as that of mitogen-activated protein kinase (MAPK) to increase the capacity for proliferation, migration, and invasion [38]. Catalase can modulate the growth rate by various mechanisms, the first obviously being its ability to detoxify H2O2. The second is its ability to bind and protect certain proteins from potential oxidative damage, such as Grb2 and SHP2, involved in integrin pathways, which in turn are themselves involved in the processes of proliferation and migration [72], [73]. As shown by many reports, catalase and mitochondrial superoxide dismutase control cell growth and migration processes in cancer cells [74], [75], [76], [77].
Surprisingly, when exposed to UVB rays, catalase can also produce ROS via NADH oxidation [78]. In addition, overexpression of catalase protects cells against DNA damage induced by UVB and X-rays [79], [80].
Catalase, as catalase-peroxidase, also possesses oxidase activity [11]. The oxidase activity requires oxygen in addition to electron donors as it is heme-dependent. Phenols (benzene derivatives), alcohols, aryl amines, and other carcinogens are substrates and/or inhibitors of oxidase function. Certain metabolites, when metabolized by catalase, are active as indole and the neurotransmitter β-phenethylamine [11]. Thus, catalase may also have additional roles such as the detoxification or activation of toxic and anti-tumor compounds. We have explored a potential role of catalase during the acquisition of cancer cell resistance to chemotherapeutic agents. To this end, we overexpressed human catalase in MCF-7 cells, a human-derived breast cancer cell line. No particular resistance against conventional chemotherapies such as doxorubicin, cisplatin, or paclitaxel was observed in cells overexpressing catalase, but cells were more resistant to the pro-oxidant combination ascorbate and menadione [74]. This association generates a redox cycling that induces ROS production (mainly H2O2) and exhibits a strong preferential ability to kill cancer cells [39], [40], [74].
Tumor cells frequently produce large amounts of reactive oxygen species [81]. This can be explained by the presence of mitochondrial defects and a decreased expression of antioxidant enzymes such as catalase or manganese superoxide dismutase [82], [83]. Instead of the phenotype observed in catalase-knockout mice and acatalasemic patients, the expression of other antioxidant enzymes is also altered in cancer cells [83]. ROS play an important role in tumorigenesis and tumor progression by inducing DNA mutations and genomic instability. On the other hand, high levels of ROS can induce cell death and alterations in redox regulation and redox signaling conducted for the development of potential anti-cancer therapies [84], [85], [86], [87].
The structure, the mechanism of enzyme activity, and the phylogeny of catalase have already been extensively reviewed [5], [88], [89], [90], [91], [92]. However, the molecular mechanisms controlling catalase expression are still poorly understood, as are those explaining the altered expression of catalase in cancer cells. Therefore, the aim of the following sections is to review current knowledge regarding the various mechanisms known to regulate catalase expression. To this end, the critical roles played by Sp1 (specificity protein 1), NF-Y (nuclear factor Y), FoxO (Forkhead box protein O), and other transcription factors such C/EBP-β (CCAAT-enhancer-binding protein β), PPARγ (peroxisome proliferator-activated receptor γ), and Oct-1 (POU2F1), as well as the pathways regulating their activities in normal and cancer cells, will be considered. Regulation at other levels, including genetic, epigenetic, and posttranscriptional modifications, will also be discussed.
Section snippets
Transcriptional regulation
The human catalase gene was first described in 1986 [2]; rat and mouse catalase genes were isolated and characterized in the next decade [93], [94]. Catalase expression is predominantly regulated at the level of transcription by transcription factors that induce or repress the transcriptional activity of human and rodent catalase promoters. Fig. 1 shows these transcription factors, specifying both the species and the exact position of the binding sites as obtained from the literature. Moreover,
Other processes regulating catalase expression
Genetic alterations and epigenetic, posttranscriptional, and posttranslational modifications have also been discussed as regulators of the transcription of the human catalase gene and are summarized in Table 2.
Developing strategies to modulate catalase protein levels
Altered expression of catalase has been associated with several diseases [21], [22]. In the particular field of cancer pathology, increased and decreased expression of catalase have both been reported.
In this context, a large body of evidence indicates that cancer cells are frequently more sensitive to oxidative stress because of their low levels of antioxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, etc.) [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]
Conclusions
In this review we have shown that the promoter region of mammalian catalases was highly conserved during evolutionary history allowing efficient binding of transcription factors NF-Y, Sp1, and WT1/Egr in the core region. Various other factors, mainly the Fox family members regulated by the Akt/PKB signaling pathway, possess conserved binding sites in vertebrate catalase promoters. Speciation events during evolution caused only small variations within these regions, conserving heme catalase as
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