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Cancer Research 67, 7368-7377, August 1, 2007. doi: 10.1158/0008-5472.CAN-07-0515
© 2007 American Association for Cancer Research

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Experimental Therapeutics, Molecular Targets, and Chemical Biology

Dual Role of Mitochondrial Reactive Oxygen Species in Hypoxia Signaling: Activation of Nuclear Factor-{kappa}B via c-SRC– and Oxidant-Dependent Cell Death

Josep M. Lluis1, Francesca Buricchi2, Paola Chiarugi2, Albert Morales1 and José C. Fernandez-Checa1

1 Liver Unit, Centro de Investigaciones Biomédicas Esther Koplowitz, Instituto de Malalties Digestives, Hospital Clinic I Provincial and CIBEREHD, Instituto Salud Carlos III, University of Barcelona, IDIBAPS and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas, Consejo Superior Investigaciones Científicas, Barcelona, Spain and 2 Department of Biochemical Sciences, Faculty of Medicine and Surgery, University of Florence, Florence, Italy

Requests for reprints: José C. Fernández-Checa, Liver Unit, Institut of Malalties Digestives, Hospital Clinic i Provincial, C/ Villarroel, 170, 08036 Barcelona, Spain. Phone: 34-93-451-5272; Fax: 34-93-451-5272; E-mail: checa229{at}yahoo.com.

Hypoxia is a prominent feature of solid tumor development and is known to stimulate mitochondrial ROS (mROS), which, in turn, can activate hypoxia-inducible transcription factor-1{alpha} and nuclear factor-{kappa}B (NF-{kappa}B). Because NF-{kappa}B plays a central role in carcinogenesis, we examined the mechanism of mROS-mediated NF-{kappa}B activation and the fate of cancer cells during hypoxia after mitochondrial reduced glutathione (mGSH) depletion. Hypoxia generated mROS in hepatoma (HepG2, H35), neuroblastoma (SH-SY5Y), and colon carcinoma (DLD-1) cells, leading to hypoxia-inducible transcription factor-1{alpha}–dependent gene expression and c-Src activation that was prevented in cells expressing a redox-insensitive c-Src mutant (C487A). c-Src stimulation activated NF-{kappa}B without I{kappa}B-{alpha} degradation due to I{kappa}B-{alpha} tyrosine phosphorylation that was inhibited by rotenone/TTFA or c-Src antagonism. The c-Src–NF-{kappa}B signaling contributed to the survival of cells during hypoxia as c-Src inhibition or p65 down-regulation by small interfering RNA–sensitized HepG2 cells to hypoxia-induced cell death. Moreover, selective mGSH depletion resulted in an accelerated and enhanced mROS generation by hypoxia that killed SH-SY5Y and DLD-1 cells without disabling the c-Src–NF-{kappa}B pathway. Thus, although mROS promote cell survival by NF-{kappa}B activation via c-Src, mROS overgeneration may be exploited to sensitize cancer cells to hypoxia. [Cancer Res 2007;67(15):7368–77]







HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2007 by the American Association for Cancer Research.