© Copyright 2008 by the Society for Neuro-Oncology
Received November 12, 2007
Accepted April 29, 2008
Basic and Translational Investigations
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Quercetin promotes degradation of survivin and thereby enhances death-receptor mediated apoptosis in glioma cells
Markus D. Siegelin 1,
David E. Reuss 1,
Antje Habel 1,
Abdelhaq Rami 2,
Andreas von Deimling 3*
1 Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg
2 Institut für Zelluläre und Molekulare Anatomie (III), Klinikum der Johann Wolfgang von Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt/Main
3 Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), Im Neuenheimer Feld 220, 69120 Heidelberg; Germany
* To whom correspondence should be addressed. E-mail: andreas.vondeimling{at}med.uni-heidelberg.de.
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Abstract |
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The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells whereas it has no effect on non-neoplastic cells. U87-MG, U251, A172, LN229 and U373 malignant gliomas cells were treated with quercetin (50-200 µM). 24 hours after treatment quercetin did not cause cytotoxicity. Combining quercetin with TNF-related apoptosis-inducing ligand (TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, LN229 glioma cells. U373 cells could not be sensitized by quercetin to TRAIL-mediated apoptosis. We demonstrated that TRAIL-induced apoptosis is 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, A172, but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin induced apoptosis was markedly reduced by over-expression of survivin. In addition, we demonstrated that upon treatment with quercetin down-regulation of survivin was also regulated by the Akt pathway. Taken together, the present study suggests that quercetin sensitizes glioma cells to death-receptor mediated apoptosis by suppression of inhibitor of apoptosis proteins survivin.
Key Words:
glioma, quercetin, TRAIL, survivin, apoptosis
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