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Originally published In Press as doi:10.1074/jbc.M111604200 on February 20, 2002

J. Biol. Chem., Vol. 277, Issue 19, 17179-17187, May 10, 2002
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Transferrin Receptor-dependent Iron Uptake Is Responsible for Doxorubicin-mediated Apoptosis in Endothelial Cells
ROLE OF OXIDANT-INDUCED IRON SIGNALING IN APOPTOSIS*

Srigiridhar KotamrajuDagger , Christopher R. Chitambar§, Shasi V. KalivendiDagger , Joy JosephDagger , and B. KalyanaramanDagger

From the Dagger  Biophysics Research Institute and Free Radical Research Center and the § Division of Neoplastic Diseases, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

In the past, investigators have successfully used iron chelators to mitigate the cardiotoxicity of doxorubicin (DOX), a widely used anticancer drug that induces reactive oxygen species (ROS), oxidative damage, and apoptosis. Although intracellular iron plays a critical role in initiating DOX-induced apoptosis, the molecular mechanism(s) that link iron, ROS, and apoptosis are still unknown. In this study, we demonstrate that apoptosis results from the exposure of bovine aortic endothelial cells to DOX and that the apoptotic cell death is accompanied by a significant increase in cellular iron (55Fe) uptake and activation of iron regulatory protein-1. Furthermore, DOX-induced iron uptake was shown to be mediated by the transferrin receptor (TfR)-dependent mechanism. Treatment with the anti-TfR antibody (IgA class) dramatically inhibited DOX-induced apoptosis, iron uptake, and intracellular oxidant formation as measured by fluorescence using dichlorodihydrofluorescein. Treatment with cell-permeable iron chelators and ROS scavengers inhibited DOX-induced cellular 55Fe uptake, ROS formation, and apoptosis. Based on these findings, we conclude that DOX-induced iron signaling is regulated by the cell surface TfR expression, intracellular oxidant levels, and iron regulatory proteins. The implications of TfR-dependent iron transport in oxidant-induced apoptosis in endothelial cells are discussed.


* This work was supported by National Institutes of Health Grants RR01008 and CA77822.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Biophysics Research Inst., Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-456-4035; Fax: 414-156-6512; E-mail: balarama@mcw.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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