期刊
CANCER SCIENCE
卷 105, 期 5, 页码 520-527出版社
WILEY
DOI: 10.1111/cas.12395
关键词
CCAAT enhancer-binding protein homologous protein; death receptor 5; quercetin; reactive oxygen species; tumor necrosis factor-related apoptosis-inducing ligand
类别
资金
- National Science Foundation of China [81373433]
- National Science Foundation of Hubei province [2012FFB01906]
- Education Department of Hubei province for Young Talents Foundation [Q20132605]
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. We investigated whether quercetin, a flavonoid, can sensitize human ovarian cancer cells to TRAIL. Results indicate that quercetin sensitized cancer cells to TRAIL. The quercetin induced expression of death receptor DR5 but did not affect expression of DR4 in cancer cells. The induction of DR5 was mediated through activation of JNK and through upregulation of a transcription factor CCAAT enhancer-binding protein homologous protein (CHOP); as silencing of these signaling molecules abrogated the effect of quercetin. 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.
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