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Xanthine Oxidase–Dependent Regulation of Hypoxia-Inducible Factor in Cancer Cells

Departments of ¹ Surgery, ² Anesthesiology, Physiology and Biophysics, and Environmental Health Sciences, and Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Corinne E. Griguer, Department of Surgery, University of Alabama at Birmingham, 1918 University Boulevard, THT 1046, Birmingham, AL 35294-0005. Phone: 205-934-7227; E-mail: cgriguer{at}uab.edu.

During chemical hypoxia induced by cobalt chloride (CoCl₂), hypoxia-inducible factor 1 (HIF1-) mediates the induction of a variety of genes including erythropoietin and vascular endothelial growth factor. We used glioma cells with oxidative phosphorylation–dependent (D54-MG) and glycolytic-dependent (U251-MG) phenotypes to monitor HIF1- regulation in association with redox responsiveness to CoCl₂ treatment. We showed that CoCl₂ increased xanthine oxidase (XO)–derived reactive oxygen species (ROS), which causes accumulation of HIF1- protein in U251-MG cells. Under these conditions, blockade of XO activity by pharmacologic (N-acetyl-L-cysteine or allopurinol) or molecular (by small interfering RNA) approaches significantly attenuated HIF1- expression. Exogenous H₂O₂ stabilizes HIF1- protein. XO was present in these cells and was the primary source of free radicals. We also showed higher XO activity in cells exposed to CoCl₂ compared with cells grown in normoxia. From the experiments shown here, we concluded that ROS were indeed generated in D54-MG cells exposed to CoCl₂ but it was unlikely that ROS participated in the hypoxic signal transduction pathways in this cell type. Possibly, cell type–dependent and stimulus-dependent factors may control ROS dependency or redox sensitivity of HIF1- and thus HIF1- activation either directly or by induction of specific signaling cascades. Our findings reveal that XO-derived ROS is a novel and critical component of HIF1- regulation in U251-MG cells, pointing toward a more general role of this transcription factor in tumor progression. (Cancer Res 2006; 66(4): 2257-63)

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