X-ray irradiation activates K+ channels via H2O2 signaling

Gibhardt, Christine S.; Roth, Bastian; Schroeder, Indra; Fuck, Sebastian; Becker, Patrick; Jakob, Burkhard; Fournier, Claudia; Moroni, Anna; Thiel, Gerhard

doi:10.1038/srep13861

Cited by 13 publications

(10 citation statements)

References 42 publications

(63 reference statements)

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“…During the last decades, multiple efforts have been made to uncover the molecular events following radiation exposure and subsequent irradiation-triggered pathways including induction of an inflammatory response ( 41 , 42 ). We have recently reported that an increase in ROS following X-irradiation with doses ≥1 Gy results in both nuclear and cytoplasmic detection in malignant cells ( 11 , 12 ). An increase in cytosolic ROS further triggers a Ca 2+ -mediated signal transduction cascade, which eventually activates Ca 2+ sensitive K + channels and causes membrane hyperpolarization ( 11 , 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…We have recently reported that an increase in ROS following X-irradiation with doses ≥1 Gy results in both nuclear and cytoplasmic detection in malignant cells ( 11 , 12 ). An increase in cytosolic ROS further triggers a Ca 2+ -mediated signal transduction cascade, which eventually activates Ca 2+ sensitive K + channels and causes membrane hyperpolarization ( 11 , 12 ). Moreover, upon contact with antigen presenting cells, mitogens or IR, T-lymphocytes respond with a rise in [Ca 2+ ] cyt ( 43 – 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…We have recently reported that an increase of reactive oxygen species (ROS) following X-irradiation of A549 cancer and human embryonic kidney HEK293 cells with doses ≥1 Gy is not restricted to the nucleus but spreads throughout the cell including the cytosol ( 11 ). The increase in cytosolic ROS further triggers a Ca 2+ -mediated signal transduction cascade and subsequent activation of Ca 2+ -sensitive channels and membrane hyperpolarization ( 11 , 12 ). Since a rise in ROS and a downstream triggering of Ca 2+ signaling cascades may comprise a more general cell response to ionizing irradiation we hypothesize that comparable signaling cascades can be triggered in other types of cells, including immune cells.…”

Section: Introductionmentioning

confidence: 99%

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Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

et al. 2018

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Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

et al. 2018

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“…Ion channels in the plasma and inner mitochondrial membrane have been reported in primary tumors to contribute to the stress response and survival of irradiated tumor cells. In particular, members of the transient receptor potential family of nonselective cation channels such as TRPV6 [ 78 ] and TRPM2 [ 79 ] or K + channels including K v 3.4 [ 80 ], K Ca 3.1 (IK Ca ) [ 79 , 81 , 82 , 83 , 84 , 85 ], and BK Ca [ 86 , 87 ] are activated in the plasma membrane by ionizing radiation. Mechanistically, these radiogenic channel activities generate Ca 2+ signals which regulate downstream targets via Ca 2+ -regulated effector proteins such as CaMKII kinases that subsequently interfere with cell motility, cell cycle control or DNA repair [ 80 , 82 , 85 ].…”

Section: Radiotherapy Of Brain Metastasesmentioning

confidence: 99%

Ion Channels in Brain Metastasis

Klumpp

Sezgın

Eckert

et al. 2016

IJMS

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Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation.

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“…20,21 In addition, X-ray irradiation can also activate K + channels in A549 and HEK293 cells. 22 Inhibition of K + efflux by using Kv channel blockers or by increasing extracellular K + concentrations inhibit stress-induced activation of signaling pathways and apoptosis in many cell types including corneal epithelial cells. 23–26 The Kv channel type activated by UV irradiation and hypoxic stress in corneal epithelial and other cells has been determined to be the Kv3.4 and Kv2.1 Kv channels by using electrophysiological and biochemical approaches.…”

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confidence: 99%

Ultraviolet Irradiation-Induced Volume Alteration of Corneal Epithelial Cells

Wang,

2016

Invest. Ophthalmol. Vis. Sci.

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PurposeThe purpose of the study is to understand how extracellular stresses, such as ultraviolet (UV) irradiation, affect corneal epithelial cells. Cell volume changes, damage to corneal epithelial integrity, and cellular responses were assessed after exposure to UVC stresses.MethodsPrimary human and rabbit corneal epithelial cells were exposed to UVC light in culture conditions. Ultraviolet C irradiation–induced changes in cell size and volume were measured by real-time microscopy and self-quenching of the fluorescent dye calcein, respectively. The effects of UVC irradiation on Src and focal adhesion kinase (FAK) phosphorylation and FAK-dependent integrin signaling were detected by ELISA, immunoblotting, and immunostaining.ResultsUltraviolet C irradiation induced both size and volume shifts in human and rabbit corneal epithelial cells. Ultraviolet C irradiation-induced decrease of cell volume elicited activation of Src and FAK, characterized by increased phosphorylations of SrcY416, FAKY397, and FAKY925. In addition, immunostaining studies showed UVC irradiation–induced increases in phosphorylation of FAK and formation of integrin β5 clustering. Application of Kv channel blockers, including 4-aminopyridine (4-AP), α-DTX, and depressing substance-1 (BDS-1), effectively suppressed UVC irradiation–induced cell volume changes, and subsequently inhibited UVC irradiation–induced phosphorylation of Src/FAK, and formation of integrin β5 clustering, suggesting UVC irradiation–induced volume changes and Src/FAK activation. Hyperosmotic pressure–induced volume decreases were measured in comparison with effects of UVC irradiation on volume and Src/FAK activation. However, Kv channel blocker, 4-AP, had no effect on hyperosmotic pressure–induced responses.ConclusionsThe present study demonstrates that UVC irradiation–induced decreases in cell volume lead to Src/FAK activation due to a rapid loss of K ions through membrane Kv channels.

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X-ray irradiation activates K+ channels via H2O2 signaling

Cited by 13 publications

References 42 publications

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

Ion Channels in Brain Metastasis

Ultraviolet Irradiation-Induced Volume Alteration of Corneal Epithelial Cells

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