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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 inhibits the activation of VEGFR2-mediated signaling pathways in HUVECs.Quercetin suppressed the activation of VEGFR2 and their down stream AKT/mTOR/p70S6K pathway triggered by VEGF in HUVECs. 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-g004: Quercetin inhibits the activation of VEGFR2-mediated signaling pathways in HUVECs.Quercetin suppressed the activation of VEGFR2 and their down stream AKT/mTOR/p70S6K pathway triggered by VEGF in HUVECs. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.

Mentions: VEGFR2 binds with VEGF that activates various downstream signaling molecules responsible for endothelial cell migration, proliferation, and survival. To understand the molecular mechanism of quercetin-mediated anti-angiogenic properties, we examined the signaling molecules and pathways using western blotting assays. VEGF treatment strongly increased the VEGFR2 phosphorylation at Ser1175 site, a reliable marker for its activity. In our study, we found that phosphorylation of VEGFR2 was suppressed by quercetin in a dose-dependent manner (Fig. 4). Quercetin significantly suppressed the activation of VEGFR2 downstream signaling molecules such as AKT, mTOR, and p70S6K, which indicated that quercetin inhibited angiogenesis through direct inhibition of VEGFR2 on the surface of endothelial cells. Extensive down regulation of phospho-AKT (Ser473), a well-known downstream target of VEGFR2, was observed at 40 µM quercetin, however total AKT levels remain unchanged (Fig. 4, upper panel western). Next, we examined the expression of phospho-mTOR (Ser2448) after quercetin exposure and the results in Figure 4 (lower panel western) revealed that phospho-mTOR levels were also decreased together with phospho-AKT. Total mTOR levels were unaltered. Furthermore, phospho-S6K (downstream target of mTOR) was decreased in a dose- dependent exposure in endothelial cells (Fig. 4, lower western). The concentrations of quercetin used for the above experiments were found to be non-toxic to endothelial cells (Fig. 1b), suggesting that the effect of quercetin on endothelial cells were not through decrease in cell viability. Collectively, the results described in this section indicated that quercetin inhibited VEGF mediated angiogenesis through VEGFR2 mediated pathway.


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 inhibits the activation of VEGFR2-mediated signaling pathways in HUVECs.Quercetin suppressed the activation of VEGFR2 and their down stream AKT/mTOR/p70S6K pathway triggered by VEGF in HUVECs. 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

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getmorefigures.php?uid=PMC3475699&req=5

pone-0047516-g004: Quercetin inhibits the activation of VEGFR2-mediated signaling pathways in HUVECs.Quercetin suppressed the activation of VEGFR2 and their down stream AKT/mTOR/p70S6K pathway triggered by VEGF in HUVECs. Proteins from different treatments was tested by western blotting and probed with specific antibodies. Experiments were repeated for three times.
Mentions: VEGFR2 binds with VEGF that activates various downstream signaling molecules responsible for endothelial cell migration, proliferation, and survival. To understand the molecular mechanism of quercetin-mediated anti-angiogenic properties, we examined the signaling molecules and pathways using western blotting assays. VEGF treatment strongly increased the VEGFR2 phosphorylation at Ser1175 site, a reliable marker for its activity. In our study, we found that phosphorylation of VEGFR2 was suppressed by quercetin in a dose-dependent manner (Fig. 4). Quercetin significantly suppressed the activation of VEGFR2 downstream signaling molecules such as AKT, mTOR, and p70S6K, which indicated that quercetin inhibited angiogenesis through direct inhibition of VEGFR2 on the surface of endothelial cells. Extensive down regulation of phospho-AKT (Ser473), a well-known downstream target of VEGFR2, was observed at 40 µM quercetin, however total AKT levels remain unchanged (Fig. 4, upper panel western). Next, we examined the expression of phospho-mTOR (Ser2448) after quercetin exposure and the results in Figure 4 (lower panel western) revealed that phospho-mTOR levels were also decreased together with phospho-AKT. Total mTOR levels were unaltered. Furthermore, phospho-S6K (downstream target of mTOR) was decreased in a dose- dependent exposure in endothelial cells (Fig. 4, lower western). The concentrations of quercetin used for the above experiments were found to be non-toxic to endothelial cells (Fig. 1b), suggesting that the effect of quercetin on endothelial cells were not through decrease in cell viability. Collectively, the results described in this section indicated that quercetin inhibited VEGF mediated angiogenesis through VEGFR2 mediated pathway.

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