Involvement of AMP-activated Protein Kinase (AMPK) in Regulation of Cell Membrane Potential in a Gastric Cancer Cell Line

Membrane potential (V mem ) is a key bioelectric property of non-excitable cells that plays important roles in regulating cell proliferation. However, the regulation of V mem itself remains largely unexplored. We found that, under nutrient starvation, during which cell division is inhibited, MKN45 gastric cancer cells were in a hyperpolarized state associated with a high intracellular chloride concentration. AMP-activated protein kinase (AMPK) activity increased, and expression of cystic fibrosis transmembrane conductance regulator (CFTR) decreased, in nutrient-starved cells. Furthermore, the increase in intracellular chloride concentration level and V mem hyperpolarization in nutrient-starved cells was suppressed by inhibition of AMPK activity. Intracellular chloride concentrations and hyperpolarization increased after over-activation of AMPK using the specific activator AICAR or suppression of CFTR activity using specific inhibitor GlyH-101. Under these conditions, proliferation of MKN45 cells was inhibited. These results reveal that AMPK controls the dynamic change in V mem by regulating CFTR and influencing the intracellular chloride concentration, which in turn influences cell-cycle progression. These findings offer new insights into the mechanisms underlying cell-cycle arrest regulated by AMPK and CFTR.