Elsevier

Free Radical Biology and Medicine

Volume 37, Issue 12, 15 December 2004, Pages 1921-1942
Free Radical Biology and Medicine

Serial Review: Redox-Active Metal Ions, Reactive Oxygen Species, and Apoptosis
Metal-induced oxidative stress and signal transduction

https://doi.org/10.1016/j.freeradbiomed.2004.09.010Get rights and content

Abstract

Occupational and environmental exposures to metals are associated with the development of various cancers. Although carcinogenesis caused by metals has been intensively investigated, the mechanisms of action, especially at the molecular level, are still unclear. Accumulating evidence indicates that reactive oxygen species generated by metals may play an important role in the etiology of disease. This review covers recent advances in (1) metal-induced generation of reactive oxygen species; (2) the receptors, kinases, and nuclear transcription factors affected by metals and metal-induced oxidative stress, including growth factor receptors, src kinase, ras signaling, mitogen-activated protein kinases, the phosphoinositide 3-phosphate/Akt pathway, nuclear transcription factor κB, activator protein 1, p53, nuclear factor of activated T cells, and hypoxia-inducible factor 1; and (3) global cellular phenomena (signal transduction, cell cycle regulation, and apoptosis) associated with metal-induced ROS production and gene expression.

Introduction

Environmental and occupational settings can offer a variety of exposures to different forms of metals. Potential sources of metal exposure include groundwater contamination, metal working, leather tanning, and mining [1], [2], [3]. Even though metals, such as iron, are required in a trace amounts for the normal function of living organisms, extensive exposure to certain metals has been linked to inflammation, cellular damage, and cancer, particularly of the lung and skin [4], [5]. These metals include arsenic (As), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), nickel (Ni), and vanadium (V). Other metals, such as lead, antinomy, and iron, have also been identified as putative carcinogens [1], [6], [7], [8], [9], [10], [11], [12]. While each metal may have its own mechanisms of action, the generation of reactive oxygen species (ROS) by metals and the resulting effects on cell signaling appear to result from a common mechanism [4], [13], [14], [15], [16], [17], [18]. One of the important members of the ROS family is the superoxide anion radical (O2radical dot), which can be dismutated to form hydrogen peroxide (H2O2) and the highly reactive hydroxyl radical (radical dotOH) in the presence of certain transition metal ions [19], [20]. Considerable evidence has emerged in recent years implicating ROS as having an important role in the initiation of cellular injury which can lead to cancer development. ROS can induce direct cellular injury, which may trigger a cascade of radical reactions enhancing secondary ROS generation. Furthermore, excessive generation of ROS may lead to the stimulation of inflammatory processes involving secretion of chemotactic factors, growth factors, proteolytic enzymes, lipoxygenases, and cycloxygenase, inactivation of antiproteolytic enzymes, and the release of signaling proteins [4], [13], [14], [15], [16], [17], [18], [20]. Cells attempt to neutralize these ROS cascades with antioxidants. There is a critical balance between oxidants and antioxidant defenses [21]. If cells are unable to maintain this redox balance, a chronic inflammatory state results. This may result in damage to the cells involved and to the surrounding tissue due to activation of signaling pathways, inflammatory cytokine production, altered gene expression, and other cellular modifications. The end result of this damage, if left unrepaired, may be metal-induced diseases including cancer. This review covers recent advances in (1) metal-induced generation of ROS, (2) the effects of metals and metal-induced oxidative stress on cancer-associated receptors, kinases and nuclear transcription factors, and (3) the effects of metals and metal-induced ROS on signal transduction, cell cycle regulation, and apoptosis.

Section snippets

Fenton-type reaction

One of the most important mechanisms of metal-mediated free radical generation is via a Fenton-type reaction [22]. In this reaction a transition metal ion reacts with H2O2 to generate radical dotOH radical and an oxidized metal ion:metaln+ + H2O2 → metal n + 1 + radical dotOH + OH.

Fenton-type reagents include chromium(III), (V), and (IV), cobalt(II), nickel(II), and vanadium(V) [23], [24], [25], [26], [27], [28], [29], [30], [31]. While all of these metal ions are able to generate radical dotOH, the efficiencies at which they

Receptors and genes affected by Metals/ROS

Although a large body of epidemiological data indicates that some metals increase cancer risk in humans, the molecular mechanisms by which carcinogenic metals act are largely unknown. This section examines the molecular pathways associated with metal-induced carcinogenesis, based primarily on cell line and animal model data. Metals and ROS have been demonstrated to affect a number of receptors and genes, including growth factor receptors, src kinase, ras signaling, mitogen-activated protein

Cellular phenomena associated with gene expression caused by Metals/ROS

The receptors and genes previously described as being affected by metals and metal-induced ROS interact via signal transduction pathways to cause major cellular events including changes in cell cycle and apoptosis. Fig. 1 provides a basic overview of how these cellular signaling components interact with metals and with one another.

Summary and conclusions

Metals are able to cause the generation of ROS through various mechanisms. Among these mechanisms, Fenton- and Haber–Weiss type reactions are most common. Through ROS-mediated reactions, metals cause DNA damage, lipid peroxidation, and protein modification. Metals also cause activation of nuclear transcription factors, activation of various signaling proteins, cell cycle arrest, and apoptosis. Metal-induced oxidative stress explains some, but not all of the carcinogenic effects of metals.

References (263)

  • X. Shi et al.

    Vanadate-mediated hydroxyl radical generation from superoxide radical in the presence of NADH: Haber–Weiss vs Fenton mechanism

    Arch. Biochem. Biophys.

    (1993)
  • X.L. Shi et al.

    The role of superoxide radical in chromium(VI)-generated hydroxyl radical: the Cr(VI) Haber–Weiss cycle

    Arch. Biochem. Biophys.

    (1992)
  • X. Shi et al.

    Cr(III)-mediated hydroxyl radical generation via Haber–Weiss cycle

    J. Inorg. Biochem.

    (1998)
  • S.S. Leonard et al.

    Cobalt-mediated generation of reactive oxygen species and its mechanism of action

    J. Inorg. Biochem.

    (1998)
  • X.L. Shi et al.

    On the mechanism of the chromate reduction by glutathione: ESR evidence for the glutathionyl radical and an isolable Cr(V) intermediate

    Biochem. Biophys. Res. Commun.

    (1988)
  • X. Shi et al.

    Chromate-mediated free radical generation from cysteine, penicillamine, hydrogen peroxide, and lipid hydroperoxides

    Biochim. Biophys. Acta

    (1994)
  • X.L. Shi et al.

    Reaction of vanadium(V) with thiols generates vanadium(IV) and thiyl radicals

    FEBS Lett.

    (1990)
  • X.L. Shi et al.

    Flavoenzymes reduce vanadium(V) and molecular oxygen and generate hydroxyl radical

    Arch. Biochem. Biophys.

    (1991)
  • X.L. Shi et al.

    NADPH-dependent flavoenzymes catalyze one electron reduction of metal ions and molecular oxygen and generate hydroxyl radicals

    FEBS Lett.

    (1990)
  • X.L. Shi et al.

    One-electron reduction of chromate by NADPH-dependent glutathione reductase

    J. Inorg. Biochem.

    (1990)
  • A.K. Nowak et al.

    New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents

    Semin. Oncol.

    (2002)
  • P. Zhang et al.

    Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro

    Mol. Cancer

    (2003)
  • W.A. Franklin et al.

    Epidermal growth factor receptor family in lung cancer and premalignancy

    Semin. Oncol.

    (2002)
  • A. Namiki et al.

    Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells

    J. Biol. Chem.

    (1995)
  • M.C. Duyndam et al.

    Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite

    J. Biol. Chem.

    (2003)
  • S.D. Dwyer et al.

    Calcium mobilization by cadmium or decreasing extracellular Na+ or pH in coronary endothelial cells

    Exp. Cell Res.

    (1991)
  • N. Gao et al.

    p38 Signalling-mediated hypoxia-inducible factor 1alpha and vascular endothelial growth factor induction by Cr(VI) in DU145 human prostate carcinoma cells

    J. Biol. Chem.

    (2002)
  • D. George

    Platelet-derived growth factor receptors: a therapeutic target in solid tumors

    Semin. Oncol.

    (2001)
  • A. Kataki et al.

    Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression

    J. Lab. Clin. Med.

    (2002)
  • R.J. Jones et al.

    Adhesion-linked kinases in cancer; emphasis on src, focal adhesion kinase and PI 3-kinase

    Eur. J. Cancer

    (2000)
  • M.C. Frame

    Src in cancer: deregulation and consequences for cell behaviour

    Biochim. Biophys. Acta

    (2002)
  • P.P. Simeonova et al.

    c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic: role in carcinogenesis

    J. Biol. Chem.

    (2002)
  • K. Balamurugan et al.

    Chromium(III)-induced apoptosis of lymphocytes: death decision by ROS and Src-family tyrosine kinases

    Free Radic. Biol. Med.

    (2002)
  • K.A. O'Hara et al.

    Selective activation of Src family kinases and JNK by low levels of chromium(VI)

    Toxicol. Appl. Pharmacol.

    (2003)
  • S. Gibson et al.

    Differential involvement of MEK kinase 1 (MEKK1) in the induction of apoptosis in response to microtubule-targeted drugs versus DNA damaging agents

    J. Biol. Chem.

    (1999)
  • F. Chen et al.

    Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite

    J. Biol. Chem.

    (2001)
  • Y. Iryo et al.

    Involvement of the extracellular signal-regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRF-CEM cells

    Biochem. Pharmacol.

    (2000)
  • J. Alam et al.

    Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells: role of p38 kinase and Nrf2 transcription factor

    J. Biol. Chem.

    (2000)
  • K.K. Elbirt et al.

    Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells: role of mitogen-activated protein kinases

    J. Biol. Chem.

    (1998)
  • J. Abe et al.

    Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase

    J. Biol. Chem.

    (1996)
  • H.S. Kim et al.

    Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence

    J. Biol. Chem.

    (2003)
  • N. Gao et al.

    Vanadate induced expression of hypoxia-inducible factor 1 and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species

    J. Biol. Chem.

    (2002)
  • K. Steenland et al.

    Review of occupational lung carcinogens

    Am. J. Ind. Med.

    (1996)
  • C. Hopenhayn-Rich et al.

    Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina

    Int. J. Epidemiol.

    (1998)
  • S. Wang et al.

    Molecular mechanisms of metal toxicity and carcinogenesis

    Mol. Cell. Biochem.

    (2001)
  • M. Desurmont

    Carcinogenic effect of metals

    Semin. Hop.

    (1983)
  • Health assessment document for cadmium. EPA 60/8-81/023

    (1981)
  • Evaluation of the potential carcinogenicity of lead and lead compounds

    (1989)
  • Integrated risk information system on beryllium

    (1999)
  • National Toxicology Program

    National Toxicology Program report on carcinogens

    (2002)
  • Cited by (0)

    This article is part of a series of reviews on “Redox-Active Metal Ions, Reactive Oxygen Species, and Apoptosis.” The full list of papers may be foubd on the home page of the journal.

    View full text