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

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.

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells

“…Akt/mTOR is regarded as a main signal adjustment pathway of protein synthesis, involved in cell proliferation, differentiation and metastasis (25). mTOR is a multi-functional kinase associated with the regulation of important cellular processes (25).…”

Early treatment with metformin induces resistance against tumor growth in adult rats

“…One of the most abundant flavonoids present in fruits, quercetin, exhibited anti-angiogenic properties that interfere with the formation of endothelial cells and was able to inhibit Walker 256 tumor growth in rats. 37,38 Interestingly, metformin treatment inhibited hyperstimulation ovarian syndrome in rats, partially due to a decrease in neovascularization associated with low levels of VEGF. Another study also Figure 1.…”

Impact of Cellular Genetic Make-up on Colorectal Cancer Cell Lines Response to Ellagic Acid: Implications of small interfering RNA

“…In this regard, recent data provided evidence on the role of Akt inactivation (inhibition of phosphorylation) in mediating EA anti-proliferative influence in HCT-15 colon cancer cells (Umesalma et al, 2015). The capability of p-Akt to phosphorylate/activate m-TOR has been described in many cancers cells (Pratheeshkumar et al, 2012;Diersch et al, 2013;Vinayak and Carlson, 2013). Inhibiting m-TOR activation is a potential target for developing anti-cancer therapeutics (Pratheeshkumar et al, 2012;Fagone et al, 2013).…”

“…The capability of p-Akt to phosphorylate/activate m-TOR has been described in many cancers cells (Pratheeshkumar et al, 2012;Diersch et al, 2013;Vinayak and Carlson, 2013). Inhibiting m-TOR activation is a potential target for developing anti-cancer therapeutics (Pratheeshkumar et al, 2012;Fagone et al, 2013). Therefore, it could be argued that the anti-proliferative effect of EA, through reducing the Akt phosphorylation, subsequently will reduce the downstream signaling of the PI3K/Akt pathway.…”