Kv3.4 potassium channel-mediated electrosignaling controls cell cycle and survival of irradiated leukemia cells

Aberrant ion channel expression in the plasma membrane is characteristic for many tumor entities and has been attributed to neoplastic transformation, tumor progression, metastasis, and therapy resistance. The present study aimed to define the function of these oncogenic channels for radioresistance of leukemia cells. Chronic myeloid leukemia cells were irradiated (0-6 Gy X ray), ion channel expression and activity, Ca2+- and protein signaling, cell cycle progression, and cell survival were assessed by quantitative reverse transcriptase-polymerase chain reaction, patch-clamp recording, fura-2 Ca2+-imaging, immunoblotting, flow cytometry, and clonogenic survival assays, respectively. Ionizing radiation-induced G(2)/M arrest was preceded by activation of K(v)3.4-like voltage-gated potassium channels. Channel activation in turn resulted in enhanced Ca2+ entry and subsequent activation of Ca2+/calmodulin-dependent kinase-II, and inactivation of the phosphatase cdc25B and the cyclin-dependent kinase cdc2. Accordingly, channel inhibition by tetraethylammonium and blood-depressing substance-1 and substance-2 or downregulation by RNA interference led to release from radiation-induced G(2)/M arrest, increased apoptosis, and decreased clonogenic survival. Together, these findings indicate the functional significance of voltage-gated K+ channels for the radioresistance of myeloid leukemia cells.