title: Quercetin promotes degradation of survivin and thereby enhances death-receptor-mediated apoptosis in glioma cells.
abstract: 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 microM). 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.
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Markus D
authors.initials: MD
authors.lastname: Siegelin
authors.forename: David E
authors.initials: DE
authors.lastname: Reuss
authors.forename: Antje
authors.initials: A
authors.lastname: Habel
authors.forename: Abdelhaq
authors.initials: A
authors.lastname: Rami
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D053218:Receptors, Death Domain; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D011794:Quercetin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex