Review ArticleSuperoxide dismutases in malignant cells and human tumors
Introduction
Free radicals and reactive oxygen and nitrogen species (ROS, RNS) are mutagenic compounds known to lead to DNA damage, favor cell transformation, and contribute to the development of a variety of malignant diseases. One of the most important free radical-generating carcinogens is cigarette smoke. One puff of cigarette smoke contains approximately 1014–16 free radicals [1]. Cigarette smoke causes lung cancer, the most common malignant disease worldwide, and also contributes to the formation of other malignant tumors. Chronic inflammatory stress, in which local oxidant burden is also increased, is known to be associated with increased cancer risk. Furthermore, several environmental carcinogens can directly generate free radicals and activate inflammatory cells to produce ROS and RNS in vivo [2], [3]. In response to these events cells can acquire multiple genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes, which will help the escape of the cells from normal growth control, cause malignant conversion, and contribute to the resistance of the cancer cells to chemotherapeutic drugs and radiation. All these events are in part mediated by oxidants and/or changes in the cellular redox state in the direction of increased oxidation. Overall, there is a well-established role for ROS, RNS, and chronic inflammation in the pathogenesis of many forms of malignancy.
Superoxide dismutases (SODs) are the only enzymes dismuting superoxide radicals. The published studies that relate superoxide dismutases to malignant cells and to human tumors show significant variability in the results. Many human tumors have been shown to express high levels of SODs, and this has been associated with aggressive tumor characteristics. Other studies have found low SOD activity in the same or different classes of tumors. In vitro studies of malignant cells have generally found that upregulation of SODs suppresses the malignant phenotype. The overall cell redox state is generally accepted as a major factor regulating the function of both normal cells and malignant cells. Regulation of the net redox state of a cell is multifactorial and complex. This review is directed at summarizing the in vivo and in vitro findings on SODs in malignancy and integrating these findings relative to the cell redox state. Most apparent inconsistencies in the published findings in this field can be harmonized when they are considered as one of multiple factors that determine the final redox state of a specific malignant cell.
Section snippets
Major oxidant pathways and their interactions with cell growth, injury, and malignant transformation
The most important oxidants in human tissues include the superoxide radical, hydrogen peroxide (H2O2), the hydroxyl radical, nitric oxide, and various nitric oxide-derived RNS such as peroxynitrite. Peroxynitrite is formed from the reaction of nitric oxide and the superoxide radical and is a potent oxidant. Exact quantitation of these various oxidants is difficult because they are short-lived and rapidly react with other compounds that participate in the regulation of the cellular redox state.
Major antioxidant pathways in mammalian cells
There are numerous mechanisms by which cells defend themselves against oxidants (Fig. 3). Superoxide dismutases decompose superoxide radicals into H2O2 and O2 [40]. The most important H2O2-scavenging enzymes and related proteins with antioxidant capability include catalase, glutathione peroxidases, glutathione reductases, enzymes associated with the synthesis of reduced glutathione (GSH) (such as γ-glutamyl cysteine synthase) [40], and a group of small cysteine-containing proteins known as
Biochemistry of superoxide dismutases and their regulation
Superoxide dismutases constitute the only mammalian antioxidant enzymes converting superoxide to H2O2. All mammalian SODs [i.e., copper–zinc SOD (CuZnSOD), manganese SOD (MnSOD), and extracellular SOD (ECSOD)] have been extensively investigated. CuZnSOD is mainly a cytosolic enzyme, but it has also been detected in cellular organelles [57], [58], [59], [60]. The distribution of CuZnSOD positions it to be the primary enzyme protecting cells against cytosolic-generated superoxide. MnSOD is
Polymorphisms of superoxide dismutases in cancer
It has become increasingly clear that individual variability of SODs due to polymorphisms may predispose to carcinogenesis. MnSOD polymorphisms have been investigated in several types of malignancies, namely in lung cancer [135], mesothelioma [136], breast cancer [137], [138], and colon carcinoma [139]. The primary MnSOD polymorphism studied is the presence of Val or Ala at position 16 in the MnSOD-targeting sequence for the mitochondria. This polymorphism is common, occurring with a frequency
Problems in characterizing antioxidant enzymes in malignant cells and solid tumors
Several factors can influence the conclusions drawn from studies of antioxidant enzymes in tumor tissues. The first and most important is the net redox state of the tissue/cell. This is the balance of oxidant production against the availability of reducing equivalents and antioxidants. Very few studies of malignant cells and solid tumors have assessed the cell redox state and there are few assessments of oxidant production in these cells. There are, however, several studies showing that
Effects of superoxide dismutases on cell growth and invasion
The association of MnSOD expression with tumor cell growth, proliferation, invasion, and resistance has been investigated in a wide variety of tumor cells, into which MnSOD has been inserted in vitro [147], [148], [149], [150], [151], [152], [153], [154], [155]. Most experimental models and cell culture studies have concluded that under these conditions MnSOD has antiproliferative effects and tumor suppressor characteristics [156]. The primary findings in these experimental studies have been
Superoxide dismutases and resistance to oxidants and drugs
Overexpression of MnSOD in cells and tissues causes increased resistance to oxidants, ROS-generating drug therapies, and radiation. A protective role of MnSOD has been confirmed both in vivo and in vitro in tissues in which MnSOD has been induced, in transgenic animals, and in cells transfected with the MnSOD gene. Prolonged treatments with TNFα, IL-1, or repeated exposures to hyperoxia cause MnSOD induction and have resulted in increased oxidant resistance and survival of rats at high oxygen
Potential differences between in vitro and in vivo studies of superoxide dismutases in cancer cells
The intracellular oxidant/antioxidant balance has multiple and complicated effects on cell growth and invasiveness, and it plays a critical role in the resistance of various cells to oxidant-generating drugs and radiation. Most previous conclusions have been obtained from cultured cells in monolayer with low SOD levels in the control cells (and probably low oxidant generation) and artificial overexpression of one enzyme (MnSOD or CuZnSOD) by transfection. These studies suggest that MnSOD is an
Expression of superoxide dismutases in human malignant diseases
To evaluate the controversies regarding expression of superoxide dismutases in malignancy, the following section provides a systematic literature review of the SOD levels in common human tumors.
Summary of superoxide dismutase expression from tumor biopsy studies
A number of malignant tumors express higher levels of MnSOD than their nonmalignant progenitor cells, with a significant association with poor prognosis. These malignancies include gastrointestinal malignancies, central nervous system tumors, cervical cancer, papillary and follicular thyroid tumors, pleural mesothelioma, and granular cell variants of renal carcinoma. In addition, poor prognosis and resistance to therapy of several malignancies—such as tumors of the central nervous system,
Conclusions and future aspects
An understanding of the expression and regulation of antioxidant enzymes in malignant tumors is necessary to develop reasonable strategies for therapeutic interventions. The majority of studies on SODs in cancer cells have used cultured cell lines or experimental models with isolated overexpression of one antioxidant enzyme such as MnSOD. These studies consistently show that manipulating cellular redox balance by an antioxidant has multiple effects on cell proliferation and survival. The major
Acknowledgements
This study was partly supported by the EVO Funding of Oulu University Hospital, University of Oulu, Cancer Society of Finland, Juselius Foundation, and Finnish Antituberculosis Association Foundation and by NIH Grant NIH P01 HL31992. The authors thank Professors Kari Alitalo, Irwin Fridovich, and Larry Oberley for comments on the manuscript.
References (279)
Nitric oxide and cell death
Biochim. Biophys. Acta
(1999)- et al.
Histochemical visualization of oxidant stress
Free Radic. Biol. Med.
(2000) - et al.
Cell division in normal and transformed cells: the possible role of superoxide and hydrogen peroxide
Med. Hypoth.
(1981) - et al.
Redox regulation of transcriptional activators
Free Radic. Biol. Med.
(1996) - et al.
Metabolic oxidative stress activates signal transduction and gene expression during glucose deprivation in human tumor cells
Free Radic. Biol. Med.
(1999) - et al.
Redox signalling and transition metals in the control of the p53 pathway
Biochem. Pharmacol.
(2000) - et al.
c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability
Mol. Cell
(2002) - et al.
Involvement of reactive oxygen intermediates in spontaneous and CD95 (Fas/APO-1)-mediated apoptosis of neutrophils
Blood
(1997) - et al.
The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse
Gastroenterology
(2001) - et al.
Reactive oxygen species regulate activation-induced T cell apoptosis
Immunity
(1999)
H2O2 induces a transient multi-phase cell cycle arrest in mouse fibroblasts through modulating cyclin D and p21Cip1 expression
J. Biol. Chem.
Reversible inactivation of the tumor suppressor PTEN by H2O2
J. Biol. Chem.
Oxygen sensing and signaling: impact on the regulation of physiologically important genes
Respir. Physiol.
Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing
J. Biol. Chem.
Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit
J. Biol. Chem.
The role of the redox protein thioredoxin in cell growth and cancer
Free Radic. Biol. Med.
Glutathione and related enzymes in multidrug resistance
Eur. J. Cancer
Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival
Hum. Pathol.
Peroxiredoxin I expression in oral cancer: a potential new tumor marker
Cancer Lett.
Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria
J. Biol. Chem.
Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene
Biochem. Biophys. Res. Commun.
Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization
J. Biol. Chem.
Synthesis and processing of the precursor for human mangano-superoxide dismutase
Biochim. Biophys. Acta
Manganese superoxide dismutase: nucleotide and deduced amino acid sequence of a cDNA encoding a new human transcript
Biochim. Biophys. Acta
Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice
J. Biol. Chem.
Superoxide dismutases
Prog. Nucleic Acid Res. Mol. Biol.
Oxidative stress, human genetic variation, and disease
Arch. Biochem. Biophys.
Isolation and characterization of complementary DNAs encoding human manganese-containing superoxide dismutase
FEBS Lett.
Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression
Free Radic. Biol. Med.
Characterization of the 5′ flanking region of the human MnSOD gene
Biochem. Biophys. Res. Commun.
Induction of Mn-superoxide dismutase by tumor necrosis factor, interleukin-1 and interleukin-6 in human hepatoma cells
Biochem. Biophys. Res. Commun.
Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response
J. Biol. Chem.
Expression of antioxidant enzymes in rat lungs after inhalation of asbestos or silica
J. Biol. Chem.
Irradiation increases manganese superoxide dismutase mRNA levels in human fibroblasts. Possible mechanisms for its accumulation
J. Biol. Chem.
Free-radical chemistry of cigarette smoke and its toxicological implications
Environ. Health Perspect.
Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer
Oncogene
Reactive oxygen species in cell signaling
Am. J. Physiol. Lung Cell Mol. Physiol.
On the origin of cancers cells
Science
Dietary carcinogens and anticarcinogens: oxygen radicals and degenerative diseases
Science
Glucose deprivation-induced oxidative stress in human tumor cells: a fundamental defect in metabolism?
Ann. N. Y. Acad. Sci.
Nuclear translocation of viral Jun but not of cellular Jun is cell cycle dependent
Proc. Natl. Acad. Sci. USA
Escape from redox regulation enhances the transforming activity of Fos
Oncogene
Apoptosis: molecular aspects of cell death and disease
Lab. Invest.
Mitochondria and apoptosis
Science
Oxygen deprivation induced cell death: an update
Apoptosis
Redox regulation of p53 during hypoxia
Oncogene
p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2
EMBO J.
Deregulated manganese superoxide dismutase expression and resistance to oxidative injury in p53-deficient cells
Cancer Res.
H(2)O(2) induces upregulation of Fas and Fas ligand expression in NGF-differentiated PC12 cells: modulation by cAMP
J. Neurosci. Res.
Hydrogen peroxide induces up-regulation of Fas in human endothelial cells
J. Immunol.
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