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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.

Yi L, Zongyuan Y, Cheng G, Lingyun Z, Guilian Y, Wei G - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

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Quercetin upregulates DR5 through mediation of reactive oxygen species (ROS). (a) Quercetin enhances cell-surface expression of DR5. Cells were treated with 200 μM quercetin for 24 h, and cell-surface expression of DR5 identified by real time-polymerase chain reaction (PCR) (upper) and western blot (lower) analysis. *P < 0.05 when compared to control. (b–d) SKOV3 cells were pre-exposed to N-acetyl-L-cysteine (NAC) for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 24 h. (b) The intracellular ROS levels were then measured by flow cytometry. (c) The whole-cell extracts were analyzed by Western blotting using DR5 antibodies. (d) Apoptosis was measured by annexin-V/PI as described in Materials and Methods. *P < 0.05 when compared to control.
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fig03: Quercetin upregulates DR5 through mediation of reactive oxygen species (ROS). (a) Quercetin enhances cell-surface expression of DR5. Cells were treated with 200 μM quercetin for 24 h, and cell-surface expression of DR5 identified by real time-polymerase chain reaction (PCR) (upper) and western blot (lower) analysis. *P < 0.05 when compared to control. (b–d) SKOV3 cells were pre-exposed to N-acetyl-L-cysteine (NAC) for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 24 h. (b) The intracellular ROS levels were then measured by flow cytometry. (c) The whole-cell extracts were analyzed by Western blotting using DR5 antibodies. (d) Apoptosis was measured by annexin-V/PI as described in Materials and Methods. *P < 0.05 when compared to control.

Mentions: Reactive oxygen species has been implicated in the induction of DR5 and plays an important role in sensitizing cancer cells to apoptosis induced by TRAIL and chemotherapeutic agents.7,8,11 First, we investigated whether quercetin induced upregulation of death receptors requires ROS. As expected, induced DR5 expression was observed by the quercetin treatment in ovarian cancer cells (Fig.3a). Moreover, quercetin induced DR5 expression and the level of ROS was suppressed by N-acetyl-L-cysteine (NAC), a ROS scavenger (Fig.3b,c). Next, we examined the role of ROS in potentiation of TRAIL-induced apoptosis by quercetin. SKOV-3 cells were treated with NAC before quercetin and TRAIL treatment, as shown in Figure3(d), the number of apoptotic cells induced by quercetin plus TRAIL was reduced from 39.5 ± 3.87% to 17.3% ± 2.01% when cells were pretreated with NAC. Overall, these results suggest that ROS play a critical role in potentiation of TRAIL-induced apoptosis by quercetin.


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.

Yi L, Zongyuan Y, Cheng G, Lingyun Z, Guilian Y, Wei G - Cancer Sci. (2014)

Quercetin upregulates DR5 through mediation of reactive oxygen species (ROS). (a) Quercetin enhances cell-surface expression of DR5. Cells were treated with 200 μM quercetin for 24 h, and cell-surface expression of DR5 identified by real time-polymerase chain reaction (PCR) (upper) and western blot (lower) analysis. *P < 0.05 when compared to control. (b–d) SKOV3 cells were pre-exposed to N-acetyl-L-cysteine (NAC) for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 24 h. (b) The intracellular ROS levels were then measured by flow cytometry. (c) The whole-cell extracts were analyzed by Western blotting using DR5 antibodies. (d) Apoptosis was measured by annexin-V/PI as described in Materials and Methods. *P < 0.05 when compared to control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4317845&req=5

fig03: Quercetin upregulates DR5 through mediation of reactive oxygen species (ROS). (a) Quercetin enhances cell-surface expression of DR5. Cells were treated with 200 μM quercetin for 24 h, and cell-surface expression of DR5 identified by real time-polymerase chain reaction (PCR) (upper) and western blot (lower) analysis. *P < 0.05 when compared to control. (b–d) SKOV3 cells were pre-exposed to N-acetyl-L-cysteine (NAC) for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 24 h. (b) The intracellular ROS levels were then measured by flow cytometry. (c) The whole-cell extracts were analyzed by Western blotting using DR5 antibodies. (d) Apoptosis was measured by annexin-V/PI as described in Materials and Methods. *P < 0.05 when compared to control.
Mentions: Reactive oxygen species has been implicated in the induction of DR5 and plays an important role in sensitizing cancer cells to apoptosis induced by TRAIL and chemotherapeutic agents.7,8,11 First, we investigated whether quercetin induced upregulation of death receptors requires ROS. As expected, induced DR5 expression was observed by the quercetin treatment in ovarian cancer cells (Fig.3a). Moreover, quercetin induced DR5 expression and the level of ROS was suppressed by N-acetyl-L-cysteine (NAC), a ROS scavenger (Fig.3b,c). Next, we examined the role of ROS in potentiation of TRAIL-induced apoptosis by quercetin. SKOV-3 cells were treated with NAC before quercetin and TRAIL treatment, as shown in Figure3(d), the number of apoptotic cells induced by quercetin plus TRAIL was reduced from 39.5 ± 3.87% to 17.3% ± 2.01% when cells were pretreated with NAC. Overall, these results suggest that ROS play a critical role in potentiation of TRAIL-induced apoptosis by quercetin.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Show MeSH
Related in: MedlinePlus