Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction

Abstract

Tumor metastasis is the primary factor causing death of cancer patients and it is a study emphasis in cancer treatment to suppress tumor metastasis by inhibiting glycolysis, which is the main way of energy supply for cell mobility in tumor. In the present study, we aimed to explore the effect of quercetin, a bioactive flavonoid, on tumor metastasis and cell glycolysis and its related functionary mechanism in breast cancer progression. Firstly, trans-well invasion assay and wound healing assay indicated that quercetin effectively suppressed cell mobility. The corresponding western blot revealed that quercetin treatment down-regulated the expression of cell migration marker proteins, such as matrix metalloproteinase 2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF). The further experiments exhibited that quercetin successfully blocked cell glycolysis by inhibiting the level of glucose uptake and the production of lactic acid, and also decreased the level of glycolysis-related proteins Pyruvate kinase M2 (PKM2), Glucose transporter1(GLUT1) and Lactate dehydrogenase A (LDHA). The above results revealed that quercetin might inhibit glycolysis to limit the migration of tumor cells by reducing the acidity of the tumor microenvironment. Moreover, our further investigation showed that quercetin induced obvious autophagy via inactivating the Akt-mTOR pathway. At the same time, the application of autophagy inhibitor 3-MA and Akt-mTOR pathway inducer IGF-1 further demonstrated that quercetin exerted inhibiting effect on cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction. At last, the in vivo experiments also showed that quercetin treatment could suppress tumor growth and metastasis, inhibit glycolysis and induce autophagy through the inhibition of p-AKT/AKT. Taken together, we firstly revealed that quercetin suppressed the progression of breast cancer by inhibiting cell mobility and glycolysis through Akt-mTOR pathway mediated autophagy induction and may provide a potential therapeutic target for breast cancer treatment.

Keywords: Akt-mTOR pathway; Autophagy; Breast Cancer; Glycolysis; Quercetin.