K+ channel signaling in irradiated tumor cells

Abstract

K channels crosstalk with biochemical signaling cascades and regulate virtually all cellular processes by adjusting the intracellular K concentration, generating the membrane potential, mediating cell volume changes, contributing to Ca signaling, and directly interacting within molecular complexes with membrane receptors and downstream effectors. Tumor cells exhibit aberrant expression and activity patterns of K channels. The upregulation of highly "oncogenic" K channels such as the Ca-activated IK channel may drive the neoplastic transformation, malignant progression, metastasis, or therapy resistance of tumor cells. In particular, ionizing radiation in doses used for fractionated radiotherapy in the clinic has been shown to activate K channels. Radiogenic K channel activity, in turn, contributes to the DNA damage response and promotes survival of the irradiated tumor cells. Tumor-specific overexpression of certain K channel types together with the fact that pharmacological K channel modulators are already in clinical use or well tolerated in clinical trials suggests that K channel targeting alone or in combination with radiotherapy might become a promising new strategy of anti-cancer therapy. The present article aims to review our current knowledge on K channel signaling in irradiated tumor cells. Moreover, it provides new data on molecular mechanisms of radiogenic K channel activation and downstream signaling events.

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

“…Electrosignaling has been demonstrated to contribute to neoplastic transformation, malignant progression and therapy resistance of cancer cells (for review see [57]). In glioblastoma cells, radiation has been shown to induce electrosignaling (for review see [58]) that involves Ca 2+ -activated BK K + channels promoting radiogenic hypermigration [37, 38] and Ca 2+ -activated IK K + channels conferring radioresistance [35, 59] in particular in mesenchymal glioblastoma stem cells [60]. While having no effect on radioresistance in the present study, VPA (750 µM) elicited Ca 2+ signals in U251 and U-87MG cells that were paralleled by phosphorylation/degradation of the phosphatase cdc25A (a regulator of G 1 /S transition and S progression [61]) and stabilization of the phosphorylated, inactive form of the mitose promoting factor cdc2.…”

“…Fura-2 Ca 2+ imaging was performed as described [35] in U251 cells superfused with NaCl solution before, during, and after administration of VPA (750 µM). Immunoblotting of VPA (0 or 750 µM for 48 h)-treated U251 cells was carried out according to [36] with the following antibodies: anti-cdc25A (#3652S, Cell Signaling, Danvers, USA), anti-p(S124)-cdc25A (#T1155, epitomics, Burlingame, USA), anti-cdc25B (#9525S Cell Signaling), anti-p(Ser187)-cdc25B (#T1162, epitomics), anti-cdc25C (#4688S, Cell Signaling), p(S216)-cdc25C (#4901S, Cell Signaling), cdc2 (#9112S, Cell Signaling) and p(Tyr15)-cdc2 (#9111S, Cell Signaling, all 1: 500) and anti-β-actin (clone AC-74, #A2228, Sigma, 1: 20.000).…”

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

“…Activation of K + channels by ionizing radiation has been reported in different tumor entities. In particular, radiationstimulated activation of Ca 2+ -dependent high conductance BK (K Ca 1.1, KCNMA1) (Steinle et al, 2011) and intermediate conductance IK (K Ca 3.1, SK4, KCNN4) K + channels (Stegen et al, 2016) occurs in glioblastoma cells. Radiation stimulated activity of the latter channels has been observed also in human T cell leukemia cells (Klumpp et al, 2016;Voos et al, 2018), in human lung adenocarcinoma (Huber et al, 2012;Roth et al, 2015), and in murine breast cancer cells (Mohr et al, 2019).…”

“…Radiation-induced activation mechanisms may comprise membrane lipid peroxidation and subsequent activation of tyrosine kinases such as src (Dittmann et al, 2009) and Pyk2 kinase (Proudfoot et al, 2018). The latter kinase has been demonstrated to directly modulate BK channels (Stegen et al, 2016). In addition, ionizing radiation has been reported to stabilize hypoxia-inducible factor-1a (HIF1a) which, in turn, upregulates auto-/paracrine chemokine signaling via the stromalcell-derived factor-1 (SDF1, CXCL12)/CXCR4 axis (Edalat et al, 2016).…”

“…Radiogenic K + channel-mediated electrosignaling reportedly acts both downstream and upstream of Ca 2+ signaling (Stegen et al, 2016). In theory, Ca 2+ entry may result in local depolarization of the plasma membrane as well as in local rise in c[Ca 2+ ] free beneath the plasma membrane which trigger activation of physically associated voltage-gated K + channels and Ca 2+ -dependent K + channels, respectively.…”