Cancer Letters

Cancer Letters

Volume 266, Issue 1, 18 July 2008, Pages 21-29
Cancer Letters

Mini-review
Redox signaling and cancer: The role of “labile” iron

https://doi.org/10.1016/j.canlet.2008.02.038Get rights and content

Abstract

Reactive oxygen species (ROS) were viewed for a long time as unavoidable by-products of normal cell catabolism. This view has recently changed and it is now apparent that ROS generation is a tightly regulated process that plays a central role in cell signaling. Thus, it is known that regulated changes in intracellular ROS levels can induce biochemical signaling processes that control basic cellular functions, such as proliferation and apoptosis which are prevalent in the development of cancer. In this short review, we will try to provide a background to this emerging field by summarizing the biochemistry of ROS-mediated cell signaling and its relation to carcinogenesis. Special emphasis will be focused on the emerging role of the so called “labile” iron (the redox-active form of iron) in ROS-mediated signaling in relation to cancer development. It is tempting to speculate that elucidation of the exact molecular mechanisms that govern ROS-mediated regulation of cell signaling will provide the basis for development of new therapeutic strategies for cancer prevention and treatment.

Introduction

Cancer development represents a multistage process in which at least three distinct stages – initiation, promotion, and progression – are involved [1]. It is initiated by the induction of a non-lethal mutation which is irreversibly fixed into the genetic material. Selective clonal expansion of the initiated cell, during the promotion stage, is characterized with increased cell growth and/or decreased capacity for apoptosis. Finally, accumulation of additional genetic changes leads to the appearance of a non-reversible malignant phenotype during the progression stage.

Strong experimental evidence supports the involvement of oxidative stress in the process of carcinogenesis [1], [2], [3], [4]. Increased formation of reactive oxygen species (ROS) in the cells can contribute to the process of carcinogenesis through either direct genotoxic effects or indirect via modification of signaling pathways that lead to altered expression of numerous genes. In particular, ROS-induced modulations of cell signaling pathways can activate transcriptional factors, like AP-1, NF-κB, HIF-1, and p53 among others [5], [6], [7], [8]. These transcriptional factors control the expression of genes the protein products of which participate in complex signal transduction pathways that can lead to cell transformation.

In this presentation, we will focus our attention mainly on the molecular mechanisms that govern ROS-induced signaling pathways that are likely to be related with cancer development. The emerging potential role of iron in cell signaling will also be discussed in this connection. Due to space limitation, reactive nitrogen species, although sharing similarities with ROS as redox signaling modulators, will not be discussed here.

Section snippets

ROS and oxidative stress

Aerobic organisms utilize molecular oxygen as a terminal electron acceptor in order to enable the removal of the electrons that are generated during the process of energy producing oxidative catabolism. Direct reduction of molecular oxygen to water is catalyzed by the last enzyme of the respiratory chain, namely “cytochrome oxidase” in a 4 electron reduction manner. Like all goods, however, oxygen can turn out to be harmful, since a small portion of the oxygen consumed in mitochondria even

Cell responses after exposure to H2O2

Mammalian cells exhibit a broad spectrum of responses toward oxidative stress which is dependent on the severity of the stress encountered. It has been shown that a dose dependent temporal up- or down-regulation of the expression of several dozens of genes are taking place when cultured cells were exposed to increased concentrations of H2O2[48]. Proteins encoded by these genes usually participate in complex signaling pathways, which by acting in a concerted way ultimately dictate concrete cell

Oxidation of cysteine residues

Extensive experimental research during the last decade has led to exiting progress regarding redox biochemistry. Thus, it is clear today that ROS, like H2O2, act as second messengers representing an integral part of the cellular signal transduction networks. This development revealed an unexpected turn in the way that oxidative stress was traditionally viewed. From the simplistic model that predicted oxidant production as inherently damaging to a more physiologically oriented view where a

Concluding remarks

ROS, like superoxide anion and H2O2 are continuously generated and removed in vivo. Thus, the steady-state concentration of these species in any particular cell type is determined by the rates of their generation and the capacity of the particular cell to remove them. When the intracellular balance between these processes is disturbed, oxidations in all cellular components are taking place and it is believed that such oxidations are mainly responsible for cancer development. Increased levels of

Acknowledgements

This research was partly supported by funds from the “Empirikion Foundation” in Athens.

References (89)

  • B. Halliwell

    Phagocyte-derived reactive species: salvation or suicide?

    Trends Biochem. Sci.

    (2006)
  • T. Finkel

    Oxidant signals and oxidative stress

    Curr. Opin. Cell. Biol.

    (2003)
  • B. Banfi et al.

    Two novel proteins activate superoxide generation by the NADPH oxidase NOX1

    J. Biol. Chem.

    (2003)
  • M. Geiszt et al.

    Proteins homologous to p47phox and p67phox support superoxide production by NAD(P)H oxidase 1 in colon epithelial cells

    J. Biol. Chem.

    (2003)
  • R. Takeya et al.

    Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases

    J. Biol. Chem.

    (2003)
  • M.R. Duchen

    Mitochondria in health and disease: perspectives on a new mitochondrial biology

    Mol. Aspects Med.

    (2004)
  • A.V. Peskin et al.

    A novel type of superoxide generating system in nuclear membranes from hepatoma 22a ascites cells

    FEBS Lett.

    (1980)
  • D.R. Davydov

    Microsomal monooxygenase in apoptosis: another target for cytochrome c signaling?

    Trends Biochem. Sci.

    (2001)
  • M. Giorgio

    Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis

    Cell

    (2005)
  • C. Rice-Evans et al.

    Free radical–lipid interactions and their pathological consequences

    Prog. Lipid Res.

    (1993)
  • D. Galaris et al.

    The role of oxidative stress in mechanisms of metal-induced carcinogenesis

    Crit. Rev. Oncol. Hematol.

    (2002)
  • A.C. Mello-Filho et al.

    Iron is the intracellular metal involved in the production of DNA damage by oxygen radicals

    Mutat. Res.

    (1991)
  • M. Chevion

    A site-specific mechanism for free radical induced biological damage: the essential role of redox-active transition metals

    Free Radic. Biol. Med.

    (1988)
  • J.M. McCord

    Iron, free radicals, and oxidative injury

    J. Nutr.

    (2004)
  • D. Galaris et al.

    On the molecular mechanism of metmyoglobin-catalyzed reduction of hydrogen peroxide by ascorbate

    Free Radic. Biol. Med.

    (1997)
  • D. Galaris et al.

    Redox cycling of myoglobin and ascorbate: a potential protective mechanism against oxidative reperfusion injury in muscle

    Arch. Biochem. Biophys.

    (1989)
  • N.G. Abraham et al.

    Heme oxygenase and the cardiovascular–renal system

    Free Radic. Biol. Med.

    (2005)
  • A.G. Wiese et al.

    Transient adaptation of oxidative stress in mammalian cells

    Arch. Biochem. Biophys.

    (1995)
  • M.D. Evans et al.

    Oxidative DNA damage and disease: induction, repair and significance

    Mutat. Res.

    (2004)
  • M. Dizdaroglu et al.

    Free radical-induced damage to DNA: mechanisms and measurement

    Free Radic. Biol. Med.

    (2002)
  • Y. Kawai et al.

    Endogenous formation of novel halogenated 2′-deoxycytidine. Hypohalous acid-mediated DNA modification at the site of inflammation

    J. Biol. Chem.

    (2004)
  • P.T. Doulias et al.

    SIN-1-induced DNA damage in isolated human peripheral blood lymphocytes as assessed by single cell gel electrophoresis (comet assay)

    Free Radic. Biol. Med.

    (2001)
  • J. Ying et al.

    Thiol oxidation in signaling and response to stress: detection and quantification of physiological and pathophysiological thiol modifications

    Free Radic. Biol. Med.

    (2007)
  • S.G. Rhee et al.

    Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins

    Curr. Opin. Cell. Biol.

    (2005)
  • A. Barbouti et al.

    Hydrogen peroxide inhibits caspase-dependent apoptosis by inactivating procaspase-9 in an iron-dependent manner

    Free Radic. Biol. Med.

    (2007)
  • W.J. Zhang et al.

    Intracellular metal ion chelators inhibit TNFalpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells

    Free Radic. Biol. Med.

    (2003)
  • S. Xiong et al.

    Signaling role of intracellular iron in NF-kappaB activation

    J. Biol. Chem.

    (2003)
  • L. Chen et al.

    Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IkappaB kinase in hepatic macrophages

    J. Biol. Chem.

    (2007)
  • C.G. Pham et al.

    Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species

    Cell

    (2004)
  • H.J. Cho et al.

    Oncogenic H-Ras enhances DNA repair through the Ras/phosphatidylinositol 3-kinase/Rac1 pathway in NIH3T3 cells. Evidence for association with reactive oxygen species

    J. Biol. Chem.

    (2002)
  • L.L. Dunn et al.

    Iron uptake and metabolism in the new millennium

    Trends Cell. Biol.

    (2007)
  • J.E. Klaunig et al.

    The role of oxidative stress in carcinogenesis

    Annu. Rev. Pharmacol. Toxicol.

    (2004)
  • B. Halliwell

    Oxidative stress and cancer: have we moved forward?

    Biochem. J.

    (2007)
  • S. Toyokuni

    Novel aspects of oxidative stress-associated carcinogenesis

    Antioxid. Redox Signal.

    (2006)
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