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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 induces endoplasmic reticulum (ER) stress signaling pathway through mediation of reactive oxygen species (ROS). (a) Cells were treated with quercetin at 200 μM for the indicated times, and equal amounts of cell lysates were subjected to western blot analysis with specific antibodies. (b) Cells were treated with quercetin for 24 h and expression of CCAAT enhancer-binding protein homologous protein (CHOP) identified by real time-polymerase chain reaction (PCR) (left) and western blot (right) analysis. *P < 0.05 when compared to control. (c,d) cells were pre-exposed to NAC and/or SP600125 for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 4 h. (c) JNK and p-JNKs were measured by western blotting. (d) Expression of CHOP identified by western blot analysis (left). The protein levels for each sample were determined as a ratio to their corresponding β-actin levels (the gray density of desired blots of CHOP/the gray density of desired blots of β-actin) (right). P < 0.05 when compared to control.
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fig04: Quercetin induces endoplasmic reticulum (ER) stress signaling pathway through mediation of reactive oxygen species (ROS). (a) Cells were treated with quercetin at 200 μM for the indicated times, and equal amounts of cell lysates were subjected to western blot analysis with specific antibodies. (b) Cells were treated with quercetin for 24 h and expression of CCAAT enhancer-binding protein homologous protein (CHOP) identified by real time-polymerase chain reaction (PCR) (left) and western blot (right) analysis. *P < 0.05 when compared to control. (c,d) cells were pre-exposed to NAC and/or SP600125 for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 4 h. (c) JNK and p-JNKs were measured by western blotting. (d) Expression of CHOP identified by western blot analysis (left). The protein levels for each sample were determined as a ratio to their corresponding β-actin levels (the gray density of desired blots of CHOP/the gray density of desired blots of β-actin) (right). P < 0.05 when compared to control.

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).


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 induces endoplasmic reticulum (ER) stress signaling pathway through mediation of reactive oxygen species (ROS). (a) Cells were treated with quercetin at 200 μM for the indicated times, and equal amounts of cell lysates were subjected to western blot analysis with specific antibodies. (b) Cells were treated with quercetin for 24 h and expression of CCAAT enhancer-binding protein homologous protein (CHOP) identified by real time-polymerase chain reaction (PCR) (left) and western blot (right) analysis. *P < 0.05 when compared to control. (c,d) cells were pre-exposed to NAC and/or SP600125 for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 4 h. (c) JNK and p-JNKs were measured by western blotting. (d) Expression of CHOP identified by western blot analysis (left). The protein levels for each sample were determined as a ratio to their corresponding β-actin levels (the gray density of desired blots of CHOP/the gray density of desired blots of β-actin) (right). P < 0.05 when compared to control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317845&req=5

fig04: Quercetin induces endoplasmic reticulum (ER) stress signaling pathway through mediation of reactive oxygen species (ROS). (a) Cells were treated with quercetin at 200 μM for the indicated times, and equal amounts of cell lysates were subjected to western blot analysis with specific antibodies. (b) Cells were treated with quercetin for 24 h and expression of CCAAT enhancer-binding protein homologous protein (CHOP) identified by real time-polymerase chain reaction (PCR) (left) and western blot (right) analysis. *P < 0.05 when compared to control. (c,d) cells were pre-exposed to NAC and/or SP600125 for 1 h, washed off, labeled with 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), and then exposed to quercetin for 4 h. (c) JNK and p-JNKs were measured by western blotting. (d) Expression of CHOP identified by western blot analysis (left). The protein levels for each sample were determined as a ratio to their corresponding β-actin levels (the gray density of desired blots of CHOP/the gray density of desired blots of β-actin) (right). P < 0.05 when compared to control.
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).

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