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K+ channel signaling in irradiated tumor cells

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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 Ca2+ 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 Ca2+-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.

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Acknowledgments

We thank Heidrun Faltin for excellent technical assistance. This work was supported by a grant from the Wilhelm-Sander-Stiftung awarded to SH and PR (2011.083.1). LE was supported by a grant from the Landesgraduierentenförderungsgesetz, Baden-Württemberg. BS and DK were supported by the DFG International Graduate School 1302 (TP T9 SH) and LK by the ICEPHA program of the University of Tübingen and the Robert-Bosch-Gesellschaft für Medizinische Forschung, Stuttgart.

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    1. Department of Radiation Oncology, University of Tübingen, Tübingen, Germany

      Benjamin Stegen, Lukas Klumpp, Milan Misovic, Marita Eckert, Dominik Klumpp & Stephan M. Huber

    2. Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Tübingen, Tübingen, Germany

      Lena Edalat & Peter Ruth

    3. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany

      Lukas Klumpp

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    B. Stegen and L. Klumpp contributed equally to this study and thus share first authorship.

    Special Issue: Ion Channels, Transporters and Cancer.

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    Stegen, B., Klumpp, L., Misovic, M. et al. K+ channel signaling in irradiated tumor cells. Eur Biophys J 45, 585–598 (2016). https://doi.org/10.1007/s00249-016-1136-z

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