Metformin Induces Mitochondria-Mediated and Endoplasmic Reticulum Stress-Mediated Apoptosis and Inhibits Angiogenesis-Related Gene Expression in Breast Cancer Cells Via Targeting VEGF-A/VEGFR2/NRP1

Abstract

Aim To investigate the apoptotic and anti-angiogenic effects of metformin in human MCF7 breast cancer cells. Methods The effect of metformin on cell viability was assessed by MTS and crystal violet assays, and its effect on cell migration was evaluated by the wound healing assay. The gene expression and protein levels of angiogenesisand apoptosis-related genes were determined by realtime polymerase chain reaction, Western blot, and flow cytometry. Results Metformin reduced the viability and migration of breast cancer cells compared with the control group. Furthermore, metformin (10 mu M) increased the apoptosis-related gene and protein expression of caspase-3, Bax, AIF, CHOP and GRP78 48 hours after treatment compared with the control group. In contrast, it significantly decreased Bcl-2 and Wee1 gene and protein expression and suppressed angiogenesis-related genes VEGFA, VEGFR2, and NRP1. Conclusions Our results suggest that metformin treatment activates apoptosis pathways and inactivates the angiogenesis pathway. Although this study was conducted in vitro and did not directly evaluate blood vessel formation, the observed downregulation of angiogenesis-related genes suggests potential anti-angiogenic activity of metformin at the gene expression level.