Metformin-activated AMPK regulates beta-catenin to reduce cell proliferation in colon carcinoma RKO cells

Abstract

Metformin can suppress cell proliferation and viability by altering mitochondrial energy metabolism and by the activation of 5 '-adenosine monophosphate-activated protein kinase (AMPK). The current study demonstrated that metformin-induced suppression of cell proliferation is further potentiated by AMPK-mediated suppression of beta-catenin-dependent wingless-type (Wnt) signaling. Treatment with metformin reduced mitochondrial oxidative phosphorylation and glycolysis, leading to an energy imbalance that may induce AMPK phosphorylation in RKO cells. Metformin treatment also decreased beta-catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with beta-catenin. The decrease in beta-catenin expression was inhibited by proteosome inhibition through phosphorylation of beta-catenin at serine 33/37. Given that nuclear translocation-associated phosphorylation of beta-catenin at serine was maintained, the association of beta-catenin with AMPK may sequester beta-catenin in the cytoplasm and lead to proteosomal degradation. Furthermore, metformin-induced suppression of cell proliferation was partially recovered by AMPK inhibition, while metformin inhibited Wnt-mediated cell proliferation and beta-catenin expression. The present results suggest that AMPK activation can suppress beta-catenin-dependent Wnt signaling by cytoplasmic sequestering of beta-catenin through AMPK, which further decreases cell proliferation in addition to metformin-induced mitochondrial dysfunction.