Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells.

Abstract

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.

• Authors: Benjamin Stegen, Lena Butz, Lukas Klumpp, Daniel Zips, Klaus Dittmann, Peter Ruth, Stephan M Huber
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 9 Pg. 1283-95 (Sep 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 26041939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• H2AX protein, human
• Histones
• Intermediate-Conductance Calcium-Activated Potassium Channels
• Potassium Channel Blockers
• Pyrazoles
• RNA, Messenger
• Radiation-Sensitizing Agents
• TRAM 34
• Dacarbazine
• Calcium
• Temozolomide

Topics

• Animals
• Calcium (metabolism)
• Cell Line, Tumor
• Combined Modality Therapy
• Dacarbazine (analogs & derivatives, pharmacology)
• Disease-Free Survival
• Female
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Knockdown Techniques
• Glioblastoma (drug therapy, metabolism, pathology, radiotherapy)
• Glioma (metabolism)
• Histones (metabolism)
• Humans
• Intermediate-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, genetics, metabolism)
• Mice
• Potassium Channel Blockers (pharmacology)
• Pyrazoles (pharmacology)
• RNA, Messenger (metabolism)
• Radiation-Sensitizing Agents (pharmacology)
• Signal Transduction (drug effects)
• Temozolomide