Cell Death and Survival Ca2þ-Activated IK Kþ Channel Blockade Radiosensitizes Glioblastoma Cells

Ca2þ-activated Kþ 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 Kþ channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiatedwith 6MVphotons and IK channel activity, Ca2þ signaling, cell cycling, residual doublestrand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34was 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 Ca2þ signaling, and induced a G2–M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G2–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 Kþ 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. 2015 AACR.