BK channel openers inhibit migration of human glioma cells

Abstract

Large-conductance Ca(2+)-activated K(+) channels (BK channels) are highly expressed in human glioma cells. However, less is known about their biological function in these cells. We used the patch-clamp technique to investigate activation properties of BK channels and time-lapse microscopy to evaluate the role of BK channel activation in migration of 1321N1 human glioma cells. In whole cells, internal perfusion with a solution containing 500 nM free Ca(2+) and external application of the BK channel opener phloretin (100 micro M) shifted the activation threshold of BK channel currents toward more negative voltages of about -30 mV, which is close to the resting potential of the cells. The concentration of intracellular Ca(2+) in fura-2-loaded 1321N1 cells was measured to be 235+/-19 nM and was increased to 472+/-25 nM after treatment with phloretin. Phloretin and another BK channel opener NS1619 (100 micro M) reduced the migration velocity by about 50%. A similar reduction was observed following muscarinic stimulation of glioma cells with acetylcholine (100 micro M). The effects of phloretin, NS1619 and acetylcholine on cell migration were completely abolished by co-application of the specific BK channel blockers paxilline (5 micro M) and iberiotoxin (100 nM). The phloretin-induced increase in intracellular Ca(2+) was unaffected by the removal of extracellular Ca(2+) and co-application of paxilline. These findings indicate that glioma cell migration was inhibited through BK channel activation, independent of intracellular Ca(2+).

Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells

“…In tumor cells, BK Ca channels regulate cell volume and shape and contribute to tumor progression and migration (3)(4)(5).…”

Antiangiogenic Effect of Rosiglitazone Is Mediated via Peroxisome Proliferator-activated Receptor γ-activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells

“…Maxi-K channels are distributed in various tissues, such as human brain tumors, vascular smooth muscle cells, and endothelial cells, and their activations were shown to inhibit migration of human glioma cells (18). The maxi-K channels are synergistically regulated by various intracellular second messengers, such as cytoplasmic Ca 2ϩ concentration, cGMP, hydrogen peroxide, and nitric oxide (NO) (19 -21).…”

Glioma Big Potassium Channel Expression in Human Cancers and Possible T Cell Epitopes for Their Immunotherapy

“…Previous in vitro studies showed that disrupted BK channel functional activity inhibits glioma cell proliferation (33,34) and migration (35,36). Earlier, we showed that prolonged activation of BK channels of T9 or U251 gliomas in vitro causes cell swelling and eventually leads to paraptosis (7,8).…”