Metformin‑activated AMPK regulates β‑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 β-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 β-catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with β-catenin. The decrease in β-catenin expression was inhibited by proteosome inhibition through phosphorylation of β-catenin at serine 33/37. Given that nuclear translocation-associated phosphorylation of β-catenin at serine was maintained, the association of β-catenin with AMPK may sequester β-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 β-catenin expression. The present results suggest that AMPK activation can suppress β-catenin-dependent Wnt signaling by cytoplasmic sequestering of β-catenin through AMPK, which further decreases cell proliferation in addition to metformin-induced mitochondrial dysfunction.