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: Mitochondrial stress is frequently accompanied by an endoplasmic reticulum stress (ER-stress) signaling.9 Upon ER-stress induction, three proteins could be activated: IRE1α, PERK, and ATF6. Phosphorylation of c-jun N-terminal kinase (JNK) and eIF2α also follows IRE1a and PERK activations, respectively. When the tumor cells were treated with quercetin for different times, it appeared that phosphorylation of IRE1α and JNK was significantly increased compared to other ER-associated proteins (Fig.4a). GRP78 and CHOP expressions were reported to occur downstream of IRE1α, our data showed that there was no effect on GRP78 expression while CHOP expression could be detected following quercetin treatment, suggesting that CHOP mediated pathway might be involved in quercetin-induced ER-stress and the subsequent apoptosis (Fig.4b).
Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.