Ionizing radiation induces migration of glioblastoma cells by activating BK K+ channels

Steinle, Marc; Palme, Daniela; Misovic, Milan; Rudner, Justine; Dittmann, Klaus; Łukowski, Robert; Ruth, Peter; Huber, Stephan M.

doi:10.1016/j.radonc.2011.05.069

Cited by 86 publications

(112 citation statements)

References 27 publications

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“…Proliferation was assessed with μ‐dishes grid‐500 (ibidi ® , Planegg/Martinsried, Germany) and xCelligence system allowing for continuous measurement by impedance readout (Steinle et al ., 2011). For the grid assay, cells were passaged and counted as described.…”

Section: Methodsmentioning

confidence: 99%

“…Aberrant K + efflux via oncogenic K Ca channels may affect multiple parameters in the breast tumour cell such as membrane potential, cytosolic Ca 2+ ([Ca 2+ ] i ), pH and cell volume (Huang and Jan, 2014; Huber, 2013). Current knowledge suggests that BK (Lallet‐Daher et al ., 2009; Parihar et al ., 2003; Stegen et al ., 2015) and SK4 (Ouadid‐Ahidouch et al ., 2004; Parihar et al ., 2003; Steinle et al ., 2011) activities are required for malignant growth of several tumour‐derived cell lines and of xenografts in immunocompromised mice, highlighting a general role of K Ca channels for cell cycle‐specific functions (Huang and Jan, 2014; Pardo and Stuhmer, 2014). Expression of SK4 and BK in cancer cells follows a cell cycle‐dependent mode (Ouadid‐Ahidouch et al ., 2004; Pardo et al ., 1998) and the mitogen‐dependent regulation of K Ca activity supports a role for both channels in malignant (Faouzi et al ., 2010; Lallet‐Daher et al ., 2009; Wang et al ., 2007a) and nonmalignant cell proliferation (Grgic et al ., 2005; Khanna et al ., 1999; Toyama et al ., 2008; Yu et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

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SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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“…The observed effect of JAK2 and V617F JAK2 on the large conductance voltage-and Ca 2ϩ -activated K ϩ channels may be relevant for proliferation, migration, and metastasis of tumor cells (15,50,52,54,63,67). However, in some cells other K ϩ channels may functionally replace the BK channels and thus inhibition of BK channels does not necessarily interfere with those functions.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of K ϩ channels and Cl Ϫ channels at the leading edge leads to KCl exit together with osmotically obligated water resulting in shrinkage of the leading process, which facilitates the movement through narrow and tortuous extracellular brain spaces (52). BK channels have further been shown to be activated by ionizing radiation and to be required for the subsequent stimulation of migration (54). On the other hand, BK channel openers have been shown to inhibit migration (27).…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the large conductance voltage- and Ca²⁺-activated K⁺ channels by Janus kinase 2

Hosseinzadeh

Almilaji

Honisch

et al. 2014

American Journal of Physiology-Cell Physiology

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The iberiotoxin-sensitive large conductance voltage- and Ca2+-activated potassium (BK) channels (maxi-K+-channels) hyperpolarize the cell membrane thus supporting Ca2+ entry through Ca2+-release activated Ca2+ channels. Janus kinase-2 (JAK2) has been identified as novel regulator of ion transport. To explore whether JAK2 participates in the regulation of BK channels, cRNA encoding Ca2+-insensitive BK channels (BKM513I+Δ899–903) was injected into Xenopus oocytes with or without cRNA encoding wild-type JAK2, gain-of-function V617FJAK2, or inactive K882EJAK2. K+ conductance was determined by dual electrode voltage clamp and BK-channel protein abundance by confocal microscopy. In A204 alveolar rhabdomyosarcoma cells, iberiotoxin-sensitive K+ current was determined utilizing whole cell patch clamp. A204 cells were further transfected with JAK2 and BK-channel transcript, and protein abundance was quantified by RT-PCR and Western blotting, respectively. As a result, the K+ current in BKM513I+Δ899–903-expressing oocytes was significantly increased following coexpression of JAK2 or V617FJAK2 but not K882EJAK2. Coexpression of the BK channel with V617FJAK2 but not K882EJAK2 enhanced BK-channel protein abundance in the oocyte cell membrane. Exposure of BK-channel and V617FJAK2-expressing oocytes to the JAK2 inhibitor AG490 (40 μM) significantly decreased K+ current. Inhibition of channel insertion by brefeldin A (5 μM) decreased the K+ current to a similar extent in oocytes expressing the BK channel alone and in oocytes expressing the BK channel and V617FJAK2. The iberiotoxin (50 nM)-sensitive K+ current in rhabdomyosarcoma cells was significantly decreased by AG490 pretreatment (40 μM, 12 h). Moreover, overexpression of JAK2 in A204 cells significantly enhanced BK channel mRNA and protein abundance. In conclusion, JAK2 upregulates BK channels by increasing channel protein abundance in the cell membrane.

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“…affecting their expression levels and contributes to the enhanced migration and invasiveness of glioma cells (Steinle et al, 2011). 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).…”

Section: Therapeutic Targeting Of Potassium Channels In Cancermentioning

confidence: 99%

Targeting potassium channels in cancer

Huang¹,

Jan²

2014

J Gen Physiol

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Ionizing radiation induces migration of glioblastoma cells by activating BK K+ channels

Cited by 86 publications

References 27 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Upregulation of the large conductance voltage- and Ca²⁺-activated K⁺ channels by Janus kinase 2

Targeting potassium channels in cancer

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Ionizing radiation induces migration of glioblastoma cells by activating BK K+ channels

Cited by 86 publications

References 27 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

Upregulation of the large conductance voltage- and Ca2+-activated K+ channels by Janus kinase 2

Targeting potassium channels in cancer

Contact Info

Product

Resources

About

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

Upregulation of the large conductance voltage- and Ca²⁺-activated K⁺ channels by Janus kinase 2