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Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X - PLoS ONE (2012)

Bottom Line: Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis.Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

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Quercetin induces cell apoptosis and inhibits the activation of AKT/mTOR/p70S6K pathway in prostate cancer cells.(a) Quercetin inhibited VEGF secretion in prostate PC-3 cancer cells. VEGF level was estimated by ELISA method. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (b) Quercetin inhibited cell viability of prostate PC-3 cancer cells. Cell viability was quantified by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin induced PC-3 cancer cell apoptosis by the cleaved-PARP analysis. PC-3 cells were treated with quercetin for 48 h, and whole cell proteins were analysed by Western blotting with antipoly (ADP-ribose) polymerase (PARP). (d) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in PC-3 cells. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.
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pone-0047516-g005: Quercetin induces cell apoptosis and inhibits the activation of AKT/mTOR/p70S6K pathway in prostate cancer cells.(a) Quercetin inhibited VEGF secretion in prostate PC-3 cancer cells. VEGF level was estimated by ELISA method. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (b) Quercetin inhibited cell viability of prostate PC-3 cancer cells. Cell viability was quantified by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin induced PC-3 cancer cell apoptosis by the cleaved-PARP analysis. PC-3 cells were treated with quercetin for 48 h, and whole cell proteins were analysed by Western blotting with antipoly (ADP-ribose) polymerase (PARP). (d) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in PC-3 cells. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.

Mentions: VEGF plays an important role in angiogenesis by promoting endothelial cell proliferation, migration, and differentiation [28]. We determined the effect of quercetin on VEGF secretion and the results are shown in Figure 5a. The quercetin treatment caused a dose-dependent and statistically significant decrease in VEGF secretion into the medium.


Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways.

Pratheeshkumar P, Budhraja A, Son YO, Wang X, Zhang Z, Ding S, Wang L, Hitron A, Lee JC, Xu M, Chen G, Luo J, Shi X - PLoS ONE (2012)

Quercetin induces cell apoptosis and inhibits the activation of AKT/mTOR/p70S6K pathway in prostate cancer cells.(a) Quercetin inhibited VEGF secretion in prostate PC-3 cancer cells. VEGF level was estimated by ELISA method. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (b) Quercetin inhibited cell viability of prostate PC-3 cancer cells. Cell viability was quantified by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin induced PC-3 cancer cell apoptosis by the cleaved-PARP analysis. PC-3 cells were treated with quercetin for 48 h, and whole cell proteins were analysed by Western blotting with antipoly (ADP-ribose) polymerase (PARP). (d) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in PC-3 cells. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475699&req=5

pone-0047516-g005: Quercetin induces cell apoptosis and inhibits the activation of AKT/mTOR/p70S6K pathway in prostate cancer cells.(a) Quercetin inhibited VEGF secretion in prostate PC-3 cancer cells. VEGF level was estimated by ELISA method. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (b) Quercetin inhibited cell viability of prostate PC-3 cancer cells. Cell viability was quantified by MTT assay. Values are means ± SD (mean of triplicate). *p<0.05 denotes a statistically significant difference from untreated controls. (c) Quercetin induced PC-3 cancer cell apoptosis by the cleaved-PARP analysis. PC-3 cells were treated with quercetin for 48 h, and whole cell proteins were analysed by Western blotting with antipoly (ADP-ribose) polymerase (PARP). (d) Quercetin inhibited the activation of AKT/mTOR/p70S6K pathway in PC-3 cells. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.
Mentions: VEGF plays an important role in angiogenesis by promoting endothelial cell proliferation, migration, and differentiation [28]. We determined the effect of quercetin on VEGF secretion and the results are shown in Figure 5a. The quercetin treatment caused a dose-dependent and statistically significant decrease in VEGF secretion into the medium.

Bottom Line: Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis.Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.

ABSTRACT
Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Show MeSH
Related in: MedlinePlus