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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
M. Niklasson, G. Maddalo, Z. Sramkova, E. Mutlu, S. Wee, P. Sekyrova, L. Schmidt, N. Fritz, I. Dehnisch, G. Kyriatzis, M. Krafcikova, BB. Carson, JM. Feenstra, VD. Marinescu, A. Segerman, M. Haraldsson, AL. Gustavsson, LG. Hammarström, A. Jenmalm...
Language English Country United States
Document type Journal Article
NLK
Free Medical Journals
from 1941 to 1 year ago
Freely Accessible Science Journals
from 1941 to 1 year ago
Open Access Digital Library
from 1941-01-01
Open Access Digital Library
from 1941-01-01
- MeSH
- Amino Acids metabolism MeSH
- Biological Transport MeSH
- Calcium Channel Blockers pharmacology MeSH
- Cell Death MeSH
- Dihydropyridines pharmacology MeSH
- Potassium Channels, Calcium-Activated antagonists & inhibitors MeSH
- Glioma drug therapy metabolism pathology MeSH
- Humans MeSH
- Mycotoxins pharmacology MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplastic Stem Cells pathology MeSH
- Brain Neoplasms drug therapy metabolism pathology MeSH
- Proteomics MeSH
- Unfolded Protein Response drug effects MeSH
- Sodium metabolism MeSH
- Calcium Channels, T-Type physiology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca(2+) and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na(+), which compromised Na(+)-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. ©2017 AACR.
Central European Institute of Technology Masaryk University Brno Czech Republic
Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden
Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden
Oncomatrix Research Lab Department of Biomedicine University of Bergen Bergen Norway
References provided by Crossref.org
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- $a Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca(2+) and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na(+), which compromised Na(+)-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. ©2017 AACR.
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