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Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells
Benjamin Stegen1, Lena Butz2, Lukas Klumpp3
1Department of Radiation Oncology, University of Tübingen, Tübingen, Germany.
Unlabelled:
Ca(2+)-activated K(+) channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K(+) channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca(2+) signaling, cell cycling, residual double-strand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in vivo in ectopic tumors. Moreover, The Cancer Genome Atlas (TCGA) was queried to expose the dependence of IK mRNA abundance on overall survival (OS) of patients with glioma. Results indicate that radiation increased the activity of IK channels, modified Ca(2+) signaling, and induced a G2-M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G2-M arrest and increased the number of γH2AX foci post-IR, suggesting that TRAM-34 mediated an increase of residual DNA double-strand breaks. Mechanistically, IK knockdown abolished the TRAM-34 effects indicating the IK specificity of TRAM-34. Finally, TRAM-34 radiosensitized ectopic glioblastoma in vivo and high IK mRNA abundance associated with shorter patient OS in low-grade glioma and glioblastoma.
Implications:
Together, these data support a cell-cycle regulatory function for IK K(+) channels, and combined therapy using IK channel targeting and radiation is a new strategy for anti-glioblastoma therapy.
Insights
Targeting intermediate-conductance calcium-activated potassium (IK) channels with TRAM-34 enhances radiation therapy for glioblastoma. This combined approach increases DNA damage and improves outcomes in preclinical models, suggesting a novel anti-glioblastoma strategy.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- Calcium-activated potassium (IK) channels play a role in glioblastoma progression.
- Ionizing radiation (IR) is a standard glioblastoma treatment.
Purpose of the Study:
- To investigate the radiosensitizing effect of IK channel inhibition in glioblastoma.
- To explore the role of IK channels in cell cycle regulation and DNA repair after radiation.
Main Methods:
- Pharmacological inhibition (TRAM-34) and genetic knockdown of IK channels in human glioblastoma cells.
- Irradiation with 6 MV photons.
- Analysis of IK channel activity, calcium signaling, cell cycle, DNA double-strand breaks (γH2AX foci), and clonogenic survival.
- In vivo studies in ectopic glioblastoma tumors.
- Analysis of The Cancer Genome Atlas (TCGA) data for IK mRNA abundance and patient overall survival (OS).
Main Results:
- IR increased IK channel activity, altered calcium signaling, and induced G2-M cell-cycle arrest.
- TRAM-34 reduced IR-induced G2-M arrest and increased residual DNA double-strand breaks.
- IK channel knockdown abolished TRAM-34's effects, confirming IK channel specificity.
- TRAM-34 demonstrated radiosensitizing effects in vivo.
- High IK mRNA levels correlated with shorter OS in glioma patients.
Conclusions:
- IK channels regulate cell cycle progression in glioblastoma cells.
- Combined IK channel targeting and radiation therapy represent a promising strategy for anti-glioblastoma treatment.
