Journal Article

Quercetin Inhibits Angiogenesis Mediated Human Prostate Tumor Growth by Targeting VEGFR- 2 Regulated AKT/mTOR/P70S6K Signaling Pathways

Son, Young-Ok, Wang, Xin, Hitron, Andrew, Xu, Mei, Shi, Xianglin, Luo, Jia, Ding, Songze, Lee, Jeong-Chae, Pratheeshkumar, Poyil, Chen, Gang, Budhraja, Amit, Zhang, Zhuo, Wang, Lei

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AKT protein / Angiogenesis / Angiogenesis Inhibitors - pharmacology / Angiogenesis Inhibitors - therapeutic use / Animal models / Animals / Antiangiogenics / Aorta / Aorta - drug effects / Apoptosis / Apoptosis - drug effects / Assaying / Biocompatibility / Biology / Brain cancer / Cancer / Cancer therapies / Cell growth / Cell Line, Tumor / Cell proliferation / Chemistry / Chick Embryo / Chorioallantoic membrane / Dosage and administration / Endothelial cells / Flavonoids / Gene Expression Regulation, Neoplastic - drug effects / Genetic aspects / Growth / Health aspects / Human Umbilical Vein Endothelial Cells - drug effects / Human Umbilical Vein Endothelial Cells - metabolism / Humans / Internal medicine / Kinases / Male / Medical research / Medicine / Metastases / Metastasis / Mice / Natural products / Neovascularization, Pathologic - prevention & control / Nutrients / Oxygen / Permeability / Phosphorylation / Prognosis / Prostate / Prostate - blood supply / Prostate - drug effects / Prostate - pathology / Prostate cancer / Prostatic Neoplasms - blood supply / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Protein kinases / Proteins / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Quercetin / Quercetin - pharmacology / Quercetin - therapeutic use / Rats / Ribosomal protein S6 / Ribosomal protein S6 kinase / Ribosomal Protein S6 Kinases, 70-kDa - genetics / Ribosomal Protein S6 Kinases, 70-kDa - metabolism / Signal transduction / Signal Transduction - drug effects / Signaling / Solid tumors / TOR protein / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / Toxicology / Tumor Burden - drug effects / Tumorigenesis / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-2 - genetics / Vascular Endothelial Growth Factor Receptor-2 - metabolism / Weight reduction / Xenograft Model Antitumor Assays / Xenografts