Mini-reviewRedox signaling and cancer: The role of “labile” iron
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)
Gene expression and the thiol redox state
Free Radic. Biol. Med.
(1999)- et al.
JunD reduces tumor angiogenesis by protecting cells from oxidative stress
Cell
(2004) Mitochondrial free radical production and cell signaling
Mol. Aspects Med.
(2004)Oxidative stress: introductory remarks
The evolution of free radicals and oxidative stress
Am. J. Med.
(2000)- et al.
Glucose oxidase-produced H2O2 induces Ca2+ dependent DNA damage in human peripheral blood lymphocytes
Free Radic. Biol. Med.
(1999) - et al.
Intracellular iron, but not copper, plays a critical role in hydrogen peroxide-induced DNA damage
Free Radic. Biol. Med.
(2001) - et al.
DNA damage and apoptosis in hydrogen peroxide-exposed Jurkat cells: bolus addition versus continuous generation of H(2)O(2)
Free Radic. Biol. Med.
(2002) - et al.
Free radical biology – terminology and critical thinking
FEBS Lett.
(2004) NADPH oxidase
Curr. Opin. Immunol.
(2004)