Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation

• Published in: Journal of cellular biochemistry 2008-12, Vol.105 (6), p.1386-1398
• Main Authors: Kim, Jin Yeop, Kim, Eun Hee, Park, Seok Soon, Lim, Jun Hee, Kwon, Taeg Kyu, Choi, Kyeong Sook
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; Apoptosis - drug effects; c-FLIPS; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism; Down-Regulation; DR5; hepatoma; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Proteasome Endopeptidase Complex - metabolism; quercetin; Quercetin - pharmacology; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Sp1 Transcription Factor - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.21958

This study demonstrates that combined treatment with subtoxic doses of quercetin (3′,3′,4′,5,7‐pentahydroxyflavone), a flavonoid found in many fruits and vegetables, plus tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) induces rapid apoptosis in TRAIL‐resistant hepatocellular carcinoma (HCC) cells. Effective induction of apoptosis by the combined treatment with quercetin and TRAIL was not blocked by overexpression of Bcl‐xL, which is known to confer resistance to various chemotherapeutic agents. These results suggest that this combined treatment may provide an attractive strategy for treating resistant HCCs. While the proteolytic processing of procaspase‐3 by TRAIL was partially blocked in various HCC cells treated with TRAIL alone, co‐treatment with quercetin efficiently recovered TRAIL‐induced caspase activation. We found that quercetin treatment of HCC cells significantly up‐regulated the mRNA and protein levels of DR5, a death receptor of TRAIL, in a transcription factor Sp1‐dependent manner. Furthermore, treatment with quercetin significantly decreased the protein levels of c‐FLIP, an inhibitor of caspase‐8, through proteasome‐mediated degradation. Finally, administration of small interfering RNA against DR5 or overexpression of c‐FLIPS, but not c‐FLIPL, significantly attenuated quercetin‐stimulated TRAIL‐induced apoptosis. Collectively, these findings show that quercetin recovers TRAIL sensitivity in various HCC cells via up‐regulation of DR5 and down‐regulation of c‐FLIPS. J. Cell. Biochem. 105: 1386–1398, 2008. © 2008 Wiley‐Liss, Inc.