Serial Review: Redox-Active Metal Ions, Reactive Oxygen Species, and ApoptosisMetal-induced oxidative stress and signal transduction☆
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 (O2−), which can be dismutated to form hydrogen peroxide (H2O2) and the highly reactive hydroxyl radical (OH) 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 OH radical and an oxidized metal ion:metaln+ + H2O2 → metal n + 1 + OH + 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 OH, 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.
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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.