A proinvasive role for the Ca²⁺‐activated K⁺ channel KCa3.1 in malignant glioma

Abstract

Glioblastoma multiforme (GBM) are highly motile primary brain tumors. Diffuse tissue invasion hampers surgical resection leading to poor patient prognosis. Recent studies suggest that intracellular Ca2+ acts as a master regulator for cell motility and engages a number of downstream signals including Ca2+-activated ion channels. Querying the REepository of Molecular BRAin Neoplasia DaTa (REMBRANDT), an annotated patient gene database maintained by the National Cancer Institute, we identified the intermediate conductance Ca2+-activated K+ channels, KCa3.1, being overexpressed in 32% of glioma patients where protein expression significantly correlated with poor patient survival. To mechanistically link KCa3.1 expression to glioma invasion, we selected patient gliomas that, when propagated as xenolines in vivo, present with either high or low KCa3.1 expression. In addition we generated U251 glioma cells that stably express an inducible knockdown shRNA to experimentally eliminate KCa3.1 expression. Subjecting these cells to a combination of in vitro and in situ invasion assays, we demonstrate that KCa3.1 expression significantly enhances glioma invasion and that either specific pharmacological inhibition with TRAM-34 or elimination of the channel impairs invasion. Importantly, after intracranial implantation into SCID mice, ablation of KCa3.1 with inducible shRNA resulted in a significant reduction in tumor invasion into surrounding brain in vivo. These results show that KCa3.1 confers an invasive phenotype that significantly worsens a patient’s outlook, and suggests that KCa3.1 represents a viable therapeutic target to reduce glioma invasion.

Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells

“…Querying the REMBRANDT patient gene data base of the National Cancer Institute has indicated an upregulation (1.5-fold greater than nontumor samples) of IK channel in more than 30% of the patients (10). Importantly, IK upregulation by the glioma correlates with a decreased survival of the patients (10).…”

“…9). Accordingly, IK protein expression in the tumor significantly correlates with poor survival of the patients with glioma (10). Similar to glioblastoma, IK channels are upregulated in a variety of further tumor entities such as prostate (11), breast (12), and pancreatic cancer (13) as well as lymphoma (14) where they have been proven to control cell cycling and tumor growth.…”

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

“…Although the present findings are not adequate to answer these questions, in those tissues where we have directly recorded BK currents or tested for coassembly between LRRC26 and BK α-subunits, LRRC26 appears to be a critical regulatory component of BK channels. Given that a large number of ion channels have been implicated in tumor growth regulation, including KCa3.1 (47,48), calcium channels (49), sodium channels (50), and a variety of K + channels (51,52), these associations raise the possibility that specific ion channels per se may not be intrinsically related to tumor growth regulation, but that some aspect of membrane potential regulation, perhaps linked to cell cycle regulation, is the determinant of whether a given ion channel may promote or impede tumor growth.…”

Molecular Mechanisms of Glioma Cell Motility

“…The KCa family of Ca 2 + -activated K + channels, especially KCa3.1, is overexpressed in 32% of the glioma patients, and its expression correlates with patient survival (126). KCa3.1 is localized at the leading edge of migrating cells, and its inhibition results in reduced migration (127,128).…”