title: Kv3.4 potassium channel-mediated electrosignaling controls cell cycle and survival of irradiated leukemia cells.
abstract: 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, Ca(2+)- and protein signaling, cell cycle progression, and cell survival were assessed by quantitative reverse transcriptase-polymerase chain reaction, patch-clamp recording, fura-2 Ca(2+)-imaging, immunoblotting, flow cytometry, and clonogenic survival assays, respectively. Ionizing radiation-induced G2/M arrest was preceded by activation of Kv3.4-like voltage-gated potassium channels. Channel activation in turn resulted in enhanced Ca(2+) entry and subsequent activation of Ca(2+)/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 G2/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.
authors: Department of Radiation Oncology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
authors: Daniela
authors: D
authors: Palme
authors: Milan
authors: M
authors: Misovic
authors: Evi
authors: E
authors: Schmid
authors: Dominik
authors: D
authors: Klumpp
authors: Helmut R
authors: HR
authors: Salih
authors: Justine
authors: J
authors: Rudner
authors: Stephan M
authors: SM
authors: Huber
mesh_terms: D017209:Apoptosis / Q000235:genetics; D016203:CDC2 Protein Kinase; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D016195:G2 Phase / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D051670:Shaw Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: D019926:Cyclin B; C492015:KCNC4 protein, human; D024642:Potassium Channels, Voltage-Gated; D051670:Shaw Potassium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D002118:Calcium