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: Based on the above results, we next investigated whether quercetin enhances TRAIL induced ovarian tumor apoptosis in vivo. To test this, we injected 5 × 106 SKOV-3 cells subcutaneously on both right and left flanks of female athymic nude mice. The treated group received quercetin by oral gavage with or without TRAIL, while the control group received PBS. Tumor volume was recorded thrice a week using vernier calipers and weight of mice was recorded twice a week. Our results show that tumor growth was reduced by the quercetin treated group, whereas only quercetin in combination with TRAIL significantly suppressed the growth of ovarian tumors (Fig.6a). Interestingly, the weight of mice from both groups did not differ significantly suggesting that quercetin was not toxic to the mice (Fig.6b). To test whether quercetin enhances TRAIL-induced tumor apoptosis was associated with ER stress by CHOP/DR5 pathway in vivo. A feature of apoptosis was observed in the tumor sections stained with immunohistochemistry that detected cleaved-caspase-3, CHOP, and DR5 is significantly increased in combined quercetin and TRAIL treated tumor (Fig.6c). Overall, these findings demonstrate that quercetin enhances TRAIL-induced apoptosis in vivo and is associated with CHOP/DR5 pathway.
Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.