Metformin Promotes AMP-activated Protein Kinase-independent Suppression of {Delta}Np63{alpha} and Inhibits Cancer Cell Viability [Signal Transduction]

The blood-glucose modifier metformin is used to treat type II diabetes and has also been shown to possess anti-cancer 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 ΔNp63α, a p53 family member involved in cell adhesion pathways, resulting in disruption of cell-matrix adhesion and in subsequent apoptosis in human squamous carcinoma cells. We further show that metformin promoted ΔNp63α protein instability independent of AMP-activated protein kinase and that WWP1, an E3 ligase of ΔNp63α, was involved in metformin-mediated down-regulation of ΔNp63α levels. In addition, we demonstrate that a combination of metformin and the glycolysis inhibitor 2-DG significantly inhibited ΔNp63α 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 in treating human squamous cell carcinoma.

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