Metformin Promotes AMP-activated Protein Kinase-independent Suppression of ΔNp63α Protein Expression and Inhibits Cancer Cell Viability

The blood glucose modifier metformin is used to treat type II diabetes and has also been shown to possess anticancer activities. Recent studies indicate that glucose deprivation can greatly enhance metformin-mediated inhibition of cell viability, but the molecular mechanism involved in this inhibition is unclear. In this study, we report that, under glucose deprivation, metformin inhibited expression of Delta Np63 alpha, a p53 family member involved in cell adhesion pathways, resulting in disruption of cell matrix adhesion and subsequent apoptosis in human squamous carcinoma cells. We further show that metformin promoted Delta Np63 alpha protein instability independent of AMP-activated protein kinase and that WWP1, an E3 ligase of Delta Np63 alpha, was involved in metformin-mediated down-regulation of Delta Np63 alpha levels. In addition, we demonstrate that a combination of metformin and the glycolysis inhibitor 2-deoxy-D-glucose significantly inhibited Delta Np63 alpha expression and also suppressed xenographic tumor growth in vivo. In summary, this study reveals a new mechanism for metformin-mediated anticancer activity and suggests a new strategy for treating human squamous cell carcinoma.