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Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways
Journal article   Open access   Peer reviewed

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

Poyil Pratheeshkumar, Amit Budhraja, Young-Ok Son, Xin Wang, Zhuo Zhang, Songze Ding, Lei Wang, Andrew Hitron, Jeong-Chae Lee, Mei Xu, …
PloS one, Vol.7(10), pp.e47516-e47516
2012
DOI: 10.1371/journal.pone.0047516
PMCID: PMC3475699
PMID: 23094058
url
https://doi.org/10.1371/journal.pone.0047516View
Published (Version of record) Open Access

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.
 Angiogenesis Inhibitors - pharmacology Angiogenesis Inhibitors - therapeutic use Animals Aorta - drug effects Apoptosis - drug effects Cell Line, Tumor Chick Embryo Gene Expression Regulation, Neoplastic - drug effects Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humans Male Mice Neovascularization, Pathologic - prevention & control Phosphorylation Prostate - blood supply Prostate - drug effects Prostate - pathology Prostatic Neoplasms - blood supply Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Quercetin - pharmacology Quercetin - therapeutic use Rats Ribosomal Protein S6 Kinases, 70-kDa - genetics Ribosomal Protein S6 Kinases, 70-kDa - metabolism Signal Transduction - drug effects TOR Serine-Threonine Kinases - genetics TOR Serine-Threonine Kinases - metabolism Tumor Burden - drug effects Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - genetics Vascular Endothelial Growth Factor Receptor-2 - metabolism Xenograft Model Antitumor Assays

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