ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity

Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K+ channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (ATP)-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of K-ATP channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, K-ATP channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G(0)/G(1) phase. Similarly, downregulation of K-ATP channels by small interfering RNA (siRNA) inhibited glioma cell proliferation. On the other hand, K-ATP channels agonist diazoxide and overexpression of K-ATP channels promoted the proliferation of glioma cells. Moreover, inhibiting K-ATP channels slowed the formation of tumor in nude mice generated by injection of glioma cells. Whereas activating K-ATP channels promoted development of tumor in vivo. The effect of K-ATP channels activity on glioma cells proliferation is mediated by extracellular signal-regulated kinase (ERK) activation. We found that activating K-ATP channel triggered ERK activation and inhibiting K-ATP channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest that K-ATP channels control glioma cell proliferation via regulating ERK pathway. We concluded that K-ATP channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.