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

Jin Yeop Kim, Eun Hee Kim, Seok Soon Park, Jun Hee Lim, Taeg Kyu Kwon, Kyeong Sook Choi
Journal of Cellular Biochemistry 2008 December 15, 105 (6): 1386-98
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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"