期刊
CANCER RESEARCH
卷 77, 期 7, 页码 1741-1752出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-2274
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资金
- Swedish Childhood Cancer Foundation
- Swedish Cancer Foundation
- Swedish Research Council
- Karolinska Institutet
- Grant Agency of the Czech Republic [GA15-20818S]
- CEITEC [LQ1601]
- Ministry of Education, Youths and Sports of the Czech Republic within National Programme for Sustainability II funds
- Netherlands Organization for Scientific Research (NWO) as part of the National Roadmap Large-Scale Research Facilities of the Netherlands [184.032.201]
- Prime XS-Consortium, seventh framework EU [XS-000158]
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 downstreamsignaling 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.
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