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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 increases tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL) induced apoptosis in human ovarian cancer cells. (a) Chemical structure of quercetin. (b,c) Cells were seeded at 4 × 104 cells/mL in a 96-well plate and treated with the indicated concentrations of quercetin for 24 h with or without TRAIL (25 ng/mL). (b) Cell viability. Cell viability was determined by cell counting kit as described in the “Materials and Methods”. (c) Flow cytometric analysis. Cells apoptosis were subjected to FACS analysis after staining with annexin-V/PI. (d) Expression of proapoptotic proteins. SKOV-3 cells treated were lysed for Western blot analysis. (e) Caspase-3 and 8 activities in vitro. SKOV-3 cell lysates were obtained from the cells treated as above. All the procedures were done according to the “Materials and Methods”.
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fig01: Quercetin increases tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL) induced apoptosis in human ovarian cancer cells. (a) Chemical structure of quercetin. (b,c) Cells were seeded at 4 × 104 cells/mL in a 96-well plate and treated with the indicated concentrations of quercetin for 24 h with or without TRAIL (25 ng/mL). (b) Cell viability. Cell viability was determined by cell counting kit as described in the “Materials and Methods”. (c) Flow cytometric analysis. Cells apoptosis were subjected to FACS analysis after staining with annexin-V/PI. (d) Expression of proapoptotic proteins. SKOV-3 cells treated were lysed for Western blot analysis. (e) Caspase-3 and 8 activities in vitro. SKOV-3 cell lysates were obtained from the cells treated as above. All the procedures were done according to the “Materials and Methods”.

Mentions: Numerous signaling molecules are known to trigger DR5 induction, including activation of inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor (ATF6),8,9 and the binding of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) transcription factor to DR5 promoter.10 Reactive oxygen species (ROS), a byproduct of normal metabolic processes and generated by exogenous sources, are integral components of cell signaling pathways.11 Important downstream mediators of ROS-induced signaling are the IRE1,12 such as JNK. ROS have also been shown to induce CHOP expression.13 Thus the agents that can modulate the expression of these signaling molecules can induce DR5 expression and might offer potential as anticancer agents. One of the potential sources of such agents includes natural products derived from “Mother Nature.” Natural products have played a significant role over the years in the discovery of cancer drugs: more than 70% of drugs are of natural origin.14 Quercetin (Fig.1a) are polyphenol chemicals found naturally in fruits, vegetables, tea and other plant-derived foods and beverages. Experimental evidence suggests that quercetin have several potential anticarcinogenic characteristics, including antioxidant, antiestrogenic, antiproliferative and anti-inflammatory properties.15


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 increases tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL) induced apoptosis in human ovarian cancer cells. (a) Chemical structure of quercetin. (b,c) Cells were seeded at 4 × 104 cells/mL in a 96-well plate and treated with the indicated concentrations of quercetin for 24 h with or without TRAIL (25 ng/mL). (b) Cell viability. Cell viability was determined by cell counting kit as described in the “Materials and Methods”. (c) Flow cytometric analysis. Cells apoptosis were subjected to FACS analysis after staining with annexin-V/PI. (d) Expression of proapoptotic proteins. SKOV-3 cells treated were lysed for Western blot analysis. (e) Caspase-3 and 8 activities in vitro. SKOV-3 cell lysates were obtained from the cells treated as above. All the procedures were done according to the “Materials and Methods”.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: Quercetin increases tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL) induced apoptosis in human ovarian cancer cells. (a) Chemical structure of quercetin. (b,c) Cells were seeded at 4 × 104 cells/mL in a 96-well plate and treated with the indicated concentrations of quercetin for 24 h with or without TRAIL (25 ng/mL). (b) Cell viability. Cell viability was determined by cell counting kit as described in the “Materials and Methods”. (c) Flow cytometric analysis. Cells apoptosis were subjected to FACS analysis after staining with annexin-V/PI. (d) Expression of proapoptotic proteins. SKOV-3 cells treated were lysed for Western blot analysis. (e) Caspase-3 and 8 activities in vitro. SKOV-3 cell lysates were obtained from the cells treated as above. All the procedures were done according to the “Materials and Methods”.
Mentions: Numerous signaling molecules are known to trigger DR5 induction, including activation of inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor (ATF6),8,9 and the binding of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) transcription factor to DR5 promoter.10 Reactive oxygen species (ROS), a byproduct of normal metabolic processes and generated by exogenous sources, are integral components of cell signaling pathways.11 Important downstream mediators of ROS-induced signaling are the IRE1,12 such as JNK. ROS have also been shown to induce CHOP expression.13 Thus the agents that can modulate the expression of these signaling molecules can induce DR5 expression and might offer potential as anticancer agents. One of the potential sources of such agents includes natural products derived from “Mother Nature.” Natural products have played a significant role over the years in the discovery of cancer drugs: more than 70% of drugs are of natural origin.14 Quercetin (Fig.1a) are polyphenol chemicals found naturally in fruits, vegetables, tea and other plant-derived foods and beverages. Experimental evidence suggests that quercetin have several potential anticarcinogenic characteristics, including antioxidant, antiestrogenic, antiproliferative and anti-inflammatory properties.15

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