Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
28087597
DOI
10.1158/0008-5472.can-16-2274
PII: 0008-5472.CAN-16-2274
Knihovny.cz E-zdroje
- MeSH
- aminokyseliny metabolismus MeSH
- biologický transport MeSH
- blokátory kalciových kanálů farmakologie MeSH
- buněčná smrt MeSH
- dihydropyridiny farmakologie MeSH
- draslíkové kanály aktivované vápníkem antagonisté a inhibitory MeSH
- gliom farmakoterapie metabolismus patologie MeSH
- lidé MeSH
- mykotoxiny farmakologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky patologie MeSH
- nádory mozku farmakoterapie metabolismus patologie MeSH
- proteomika MeSH
- signální dráha UPR účinky léků MeSH
- sodík metabolismus MeSH
- vápníkové kanály - typ T fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aminokyseliny MeSH
- blokátory kalciových kanálů MeSH
- dihydropyridiny MeSH
- draslíkové kanály aktivované vápníkem MeSH
- mykotoxiny MeSH
- niguldipine MeSH Prohlížeč
- sodík MeSH
- tremortin MeSH Prohlížeč
- vápníkové kanály - typ T 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 Ca2+ 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 Neurosurgery Haukeland University Hospital Bergen Norway
Department of Physiology and Biophysics Weill Cornell Medical College New York New York
Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden
Oncomatrix Research Lab Department of Biomedicine University of Bergen Bergen Norway
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