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.

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

“…In leukemia, IR-induced co-activation of both Ca 2þ -permeable channels and K þ channels gives rise to Ca 2þ signals that induce cell-cycle arrest via CaMKII-mediated inhibition of the mitosis-promoting factor cdc2. Notably, pharmacologic K þ channel blockade overrides cell-cycle arrest of irradiated leukemia cells resulting in radiosensitization (27). In the present study, irradiated cells exhibited an elevated steady state i [Ca 2þ ] free that was almost as double as high as the resting i [Ca 2þ ] free of unirradiated cells (see Fig.…”

“…The present study demonstrates IR-induced Ca 2þ signaling and activation of Ca IR-induced modifications of Ca 2þ signaling and/or K þ channel activity have been reported by our group in different tumor entities such as lung adenocarcinoma (28), leukemia cells (27,29), or glioblastoma (21). In lung adenocarcinoma, K þ channels contribute to an elevated glucose uptake by the irradiated cells.…”

“…This suggests that a shift in the Ca 2þ leak/pump equilibrium of the plasma membrane accounted for the observed IR-induced i[Ca 2þ ] free increase. K þ channels have been shown to regulate the cell cycle in irradiated tumor cells (27). Therefore, we analyzed by flow cytometry, the incorporation of the base analogue EdU by irradiated (0 or 2 Gy) T98G cells within the first 6 hours after IR.…”

Role of ion channels in ionizing radiation-induced cell death

“…Studies of our laboratory indicate that survival of irradiated human leukemia cells critically depends on Ca 2+ signaling involving radiogenic activation of TRPV5/6-like nonselective cation and K v 3.4 voltage-gated K + channels [40,41]. The nonselective cation channels in concert with K v 3.4 generate radiogenic Ca 2+ signals that contribute to G 2 /M cell cycle arrest by CaMKII-mediated inhibition of the phosphatase cdc25B.…”

Targeting potassium channels in cancer

“…Radiation treatment can also increase Kv3.4 channel activity in leukemic cells to promote calcium entry and CaMKII-dependent cancer cell survival (Palme et al, 2013). Low-dosage radiation induces voltage-dependent potassium channel activity that is otherwise not present in human lung adenocarcinoma cells (Kuo et al, 1993).…”