Quercetin enhances TRAIL-induced apoptosis in prostate cancer cells via increased protein stability of death receptor 5.
OBJECTIVE
Quercetin has been shown to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of prostate cancer cells via mechanisms that include upregulation of death receptor (DR) 5, a protein reported to play an important role in sensitizing cancer cells to apoptosis. We aimed to determine the specific mechanisms underlying quercetin-induced DR5 expression.


METHODS
Human prostate cancer cells were exposed to quercetin and TRAIL. Trypan blue assays and terminal transferase dUTP nick-end labeling (TUNEL) assays evaluated changes in TRAIL resistance after quercetin treatment, and flow cytometry examined quercetin-induced death receptor expression in DU-145 cells. Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and transiently transfection were utilized to confirm apoptotic patterns of prostate cancer cells.


RESULTS
After stimulation with quercetin, DU-145 cells exhibited stronger sensitization to TRAIL. Quercetin treatment enhanced TRAIL-induced activation proteins in the caspase pathway, such as poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-9. Quercetin dose-dependently increased DR5 levels in prostate cancer cells, which was mediated by increased transcription and protein stability, but not mRNA stability. Ectopic expression of DR5 dose-dependently increased TRAIL-induced apoptosis.


CONCLUSIONS
Our results showed that the role of quercetin and TRAIL combination therapy may provide a novel strategy for treating prostate cancer by overcoming critical mechanisms of apoptosis resistance.
Jung
Young-Hwa
YH
Department of Molecular Biology and Immunology, College of Medicine, Kosin University, Busan 602-703, Korea.
Heo
Jeonghoon
J
Lee
Yong J
YJ
Kwon
Taeg Kyu
TK
Kim
Young-Ho
YH
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D011794:Quercetin