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Inhibition of T-type calcium channel disrupts Akt signaling and promotes apoptosis in glioblastoma cells.
Abstract
Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resitant to both radio- and chemotherapy regimens and novel approaches to treatment are needed. T-type calcium channels are one type of low voltage-gated channel (LVCC) involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM. In this study, we found that inhibition of T-type Ca channels in GBM cells significantly reduced their survival and resistance to therapy. Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential, but also induced apoptosis. In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the mTORC2/Akt pathway. This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation. The apoptotic response was specific for T-type Ca channels, as inhibition of L-type Ca channels did not induce similar effects. Our results implicate T-type Ca channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy.
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Authors (8)
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Nicholas C.K. Valerie
- University of Virginia, Charlottesville Department of Radiation Oncology,
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Barbara Dziegielewska
- University of Virginia, Charlottesville Department of Radiation Oncology
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Amol S. Hosing
- University of Virginia, Charlottesville Department of Radiation Oncology
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Lloyd S. Gray
- TAU Therapeutics LLC ..
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David L. Brautigan
- University of Virginia School of Medicine Department of Microbiology, Immunology and Cancer Biology & Center for Cell Signaling,
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James M. Larner
- University of Virginia, Charlottesville, University of Virginia School of Medicine Department of Radiation Oncology, Cancer Center
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Jaroslaw Dziegielewski
- University of Virginia, Charlottesville, University of Virginia School of Medicine Department of Radiation Oncology, Cancer Center
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Details
- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
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BIOCHEMICAL PHARMACOLOGY
no. 85,
edition 7,
pages 888 - 897,
ISSN: 0006-2952 - Language:
- English
- Publication year:
- 2013
- Bibliographic description:
- Valerie N., Dziegielewska b., Hosing A., Augustin E., Gray ., Brautigan D., Larner J., Dziegielewski j.: Inhibition of T-type calcium channel disrupts Akt signaling and promotes apoptosis in glioblastoma cells.// BIOCHEMICAL PHARMACOLOGY. -Vol. 85, iss. 7 (2013), s.888-897
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.bcp.2012.12.017
- Verified by:
- Gdańsk University of Technology
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