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

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 and nuclear factor-B (NF-B). Because NF-B plays a central role in carcinogenesis, we examined the mechanism of mROS-mediated NF-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–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-B without IB- degradation due to IB- tyrosine phosphorylation that was inhibited by rotenone/TTFA or c-Src antagonism. The c-Src–NF-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-B pathway. Thus, although mROS promote cell survival by NF-B activation via c-Src, mROS overgeneration may be exploited to sensitize cancer cells to hypoxia. [Cancer Res 2007;67(15):7368–77]

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