Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamycin (mTOR) Signaling Cascade

Abstract

The Akt/adenosine monophosphate protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has emerged as a critical signaling nexus for regulating cellular metabolism, energy homeostasis, and cell growth. Thus, dysregulation of this pathway contributes to the development of metabolic disorders such as obesity, type 2diabetes, and cancer. We previously reported that a combination of grape polyphenols (resveratrol, quercetin and catechin: RQC), at equimolar concentrations, reduces breast cancer (BC) growth and metastasis in nude mice, and inhibits Akt and mTOR activities and activates AMPK, an endogenous inhibitor of mTOR, in metastatic BC cells. The objective of the present study was to determine the contribution of individual polyphenols to the effect of combined RQC on mTOR signaling. Metastatic BC cells were treated with RQC individually or in combination, at various concentrations, and the activities (phosphorylation) of AMPK, Akt, and the mTOR downstream effectors, p70S6 kinase (p70S6K) and 4E binding protein (4EBP1), were determined by Western blot. Results show that quercetin was the most effective compound for Akt/mTOR inhibition. Treatment with quercetin at 15μM had a similar effect as the RQC combination in the inhibition of BC cell proliferation, apoptosis, and migration. However, cell cycle analysis showed that the RQC treatment arrested BC cells in the G1 phase, while quercetin arrested the cell cycle in G2/M. In vivo experiments, using SCID mice with implanted tumors from metastatic BC cells, demonstrated that administration of quercetin at 15mg/kg body weight resulted in a ~70% reduction in tumor growth. In conclusion, quercetin appears to be a viable grape polyphenol for future development as an anti BC therapeutic.

Quercetin Inhibits Breast Cancer Stem Cells via Downregulation of Aldehyde Dehydrogenase 1A1 (ALDH1A1), Chemokine Receptor Type 4 (CXCR4), Mucin 1 (MUC1), and Epithelial Cell Adhesion Molecule (EpCAM)

“…We also discovered that MDA-MB-231 cells treated with quercetin had a lower proportion of G1 phase cells and a higher proportion of G2/M phase cells compared to those not treated with quercetin ( Figure 3 ). These results are similar to those previously reported [ 25 ]. Quercetin-mediated cell cycle arrest in the G2/M phase is possibly associated with upregulation of cyclin D1, which has been reported in other cell lines [ 26 , 27 ].…”

Flavonoids, bioactive components of propolis, exhibit cytotoxic activity and induce cell cycle arrest and apoptosis in human breast cancer cells MDA-MB-231 and MCF-7 – a comparative study

“…Our results are also in line with Li et al (84); the authors who also used NAR, to induce apoptosis in MDA-MB-231 cells. After QUE treatment, Choi et al (85) detected apoptosis in MDA-MB-453 cells, another TNBC line, similar to research by Rivera et al (86) and in line with our own results on different breast cancer cells.…”

Quercetin shows anti‐tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway

“…2,3 Studies have shown that flavonoids can play its roles through many genes and pathways, for example, nuclear factor kappa B(NF-kB), phosphatidylinositol3'-kinase (PI3K), signal transducers and activators of transcription (STAT), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), to protect human health. [4][5][6] Quercetin(3,3′,4′,5,7-Pentahydroflavone,QE) is a typical flavonoid that shows significant effects on blocking the development of breast cancer, 7 ovarian cancer, 8 carcinoma of colon and rectum, 9 gastric cancer, 10 and hepatic cancer. Our previous studies have shown that quercetin could protect the liver from concanavalin A-induced acute hepatitis, ischemia reperfusion injury, and fibrosis.…”