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First published on October 29, 2008
This version was published on January 1, 2009
Neuro Oncol 2009 11(2):122-131; DOI:10.1215/15228517-2008-085
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Duke University Press

Basic and Translational Investigations

Quercetin promotes degradation of survivin and thereby enhances death-receptor–mediated apoptosis in glioma cells

Markus D. Siegelin, David E. Reuss, Antje Habel, Abdelhaq Rami and Andreas von Deimling

Department of Neuropathology, University Hospital Heidelberg, Heidelberg (M.D.S., D.E.R., A.H., A.V.); Institute for Cellular and Molecular Anatomy III, Department of Medicine, Johann Wolfgang von Goethe University Hospital, Frankfurt (A.R.); Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), Heidelberg (A.V.); Germany

Address correspondence to Andreas von Deimling, Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany (andreas.vondeimling{at}med.uni-heidelberg.de).

The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells, whereas it has no effect on nonneoplastic cells. U87-MG, U251, A172, LN229, and U373 malignant glioma cells were treated with quercetin (50–200 µM). Quercetin did not cause cytotoxicity 24 h after treatment. Combining quercetin with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, and LN229 glioma cells; U373 cells could not be sensitized by quercetin to TRAIL-mediated apoptosis. TRAIL-induced apoptosis was enhanced by quercetin-induced reduction of survivin protein levels. Upon treatment with quercetin, the protein level of survivin was strongly suppressed in U87-MG, U251, and A172 but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin–induced apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with quercetin, downregulation of survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes glioma cells to death-receptor–mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.

Key Words: apoptosis • glioma • quercetin • survivin • TRAIL


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