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

Abstract

Ca 2þ -activated K þ channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K þ channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca 2þ signaling, cell cycling, residual doublestrand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in vivo in ectopic tumors. Moreover, The Cancer Genome Atlas (TCGA) was queried to expose the dependence of IK mRNA abundance on overall survival (OS) of patients with glioma. Results indicate that radiation increased the activity of IK channels, modified Ca 2þ signaling, and induced a G 2 -M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G 2 -M arrest and increased the number of gH2AX foci post-IR, suggesting that TRAM-34 mediated an increase of residual DNA double-strand breaks. Mechanistically, IK knockdown abolished the TRAM-34 effects indicating the IK specificity of TRAM-34. Finally, TRAM-34 radiosensitized ectopic glioblastoma in vivo and high IK mRNA abundance associated with shorter patient OS in low-grade glioma and glioblastoma.Implications: Together, these data support a cell-cycle regulatory function for IK K þ channels, and combined therapy using IK channel targeting and radiation is a new strategy for anti-glioblastoma therapy. Mol Cancer Res; 13(9); 1283-95. Ó2015 AACR.

Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses

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Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells

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Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

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