Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway.
Bottom Line: Upregulation of DR5 was mediated through the generation of reactive oxygen species (ROS), as ROS scavengers reduced the effect of quercetin on JNK activation, CHOP upregulation, DR induction, TRAIL sensitization, downregulated the expression of cell survival proteins and upregulated the proapoptotic proteins.Furthermore, quercetin enhances TRAIL mediated inhibition of tumor growth of human SKOV-3 xenograft was associated with induction of apoptosis, activation of caspase-3, CHOP and DR5.Overall, our data suggest that quercetin enhances apoptotic death of ovarian cancer cells to TRAIL through upregulation of CHOP-induced DR5 expression following ROS mediated endoplasmic reticulum-stress.
Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.Show MeSH
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Mentions: Many of the mitochondrial cell survival proteins such as XIAP, Bcl-2, Bcl-xL, and cFLIP have been shown to cause TRAIL resistance.21,22 To see the intrinsic activity of quercetin in mitochondria, SKOV-3 cells were treated with quercetin and the level of intracellular ATP was measured. As expected, quercetin dose dependently reduced ATP formation (Fig.2a). Correspondingly, numerous pieces of evidence have shown that apoptosis is associated with the increase of intracellular ROS levels and the loss of ΔΨm, of mitochondria. The results indicated that quercetin significantly increased the intracellular ROS levels and decreased the levels of ΔΨm in SKOV-3 cells in a dose-dependent course (Fig.2b,c). These results indicate that quercetin significantly affects mithochondrial membrane potential. In addition, quercetin obviously inhibited Bcl-2, Bcl-xL, XIAP, and Survivin expression, whereas FLICE like inhibitory protein (cFLIP) was not significantly affected (Fig.2d). These results raised the possibility that quercetin induced mitochondrial dysfunction and downregulation of some cell survival proteins could contribute to the enhancement of TRAIL induced apoptosis (Fig. S2a–d).
Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.