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

Abstract

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.

Lipoxin A4-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair

“…Consistent with similar results obtained in corneal epithelium (20), we have shown that LXA 4 triggered ERK phosphorylation, which mediates LXA 4 -induced proliferation and repair in both non-CF and CF airway epithelial cells. The opposite role of glibenclamide and pinacidil on ERK phosphorylation is consistent with a regulation of ERK activity downstream to K ATP channel activity and recent data showing that that K ATP channels could induce ERK phosphorylation in neuronal and cardiac models (17).…”

“…In particular, potassium (K ϩ ) channels have been shown in numerous cell types to be involved in cell migration and proliferation (22,26,30,32,44,45). Recent research in glioma tumor cells shows that K ATP channels promote cell proliferation through ERK phosphorylation (17).…”

MEK/ERK inhibitor U0126 enhanced salt stress-induced programmed cell death in Thellungiella halophila suspension-cultured cells

“…The upregulation of mitochondrial K ATP channels may activate ERKs. Their activation is associated with cell proliferation and cell survival (Huang et al 2009). Alternatively, salt stress will activate ERKs directly, which leads to the preservation of cell viability.…”

Mitochondrial KATP Channels Control Glioma Radioresistance by Regulating ROS-Induced ERK Activation

“…Cell transfection was performed as described previously [17]. The sequences of siRNA1 against Kir6.2 are 5-CCAAGAAA GGCAACUGCAATT-3 (sense) and 5-UUGCAGUUGCCU UUCUUG GTT-3 (antisense), siRNA2 are 5-CCAUUGUA GCU GAGGAGGATT-3 (sense) and 5-UCCUCCU CAGC UACAAUGGTT-3 (antisense), and non-silencing RNA are 5-UUCUCCGAACGUGUCACGUTT-3 (sense) and 5-ACGU GACACGU UCGGA GAATT-3 (antisense).…”

“…For example, calcium channels are activated in ischemic neuronal cell death and calcium channel blockers are used in stroke treatment [12]. Considerable evidence exists for the contribution of ion channels to the development and growth of malignant glioma [13][14][15][16][17]. For example, the chloride channel blocking peptide is currently being evaluated in a multi-center phase II clinical trial for glioma [16].…”