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: CHOP, a resident chaperone in the ER, is a key regulator of DR5.10,23 To determine in more detail how quercetin modulates the expression of DR5, SKOV-3 cells were treated with quercetin for 24 h and qPCR analysis was performed for the determination of CHOP expression. Quercetin significantly increased CHOP expression in a dose-dependent manner (Fig.4b). To further confirm that CHOP regulates DR5 expression, SKOV-3 cells were transfected with CHOP siRNA, followed by quercetin. Knockdown of CHOP in SKOV-3 cells diminished quercetin induced increased production of DR5 (Fig.5a). Moreover, CHOP knockdown greatly reduced caspase-3 and 9 activation as well as PARP cleavage in cells treated with both quercetin and TRAIL (Fig.5b). Fluorescence-activated cell sorting analyses showed also that cell apoptosis was restored upon the depletion of CHOP by siRNA treatment (Fig.5c). These findings suggest that CHOP upregulates DR5 expression, which could be one of the mechanisms by which quercetin enhances TRAIL induced apoptosis in ovarian cancer cells.
Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.