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Figure S4 from Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses

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posted on 2023-03-31, 01:25 authored by Mia Niklasson, Gianluca Maddalo, Zuzana Sramkova, Ercan Mutlu, Shimei Wee, Petra Sekyrova, Linnéa Schmidt, Nicolas Fritz, Ivar Dehnisch, Gregorios Kyriatzis, Michaela Krafcikova, Brittany B. Carson, Jennifer M. Feenstra, Voichita D. Marinescu, Anna Segerman, Martin Haraldsson, Anna-Lena Gustavsson, Lars G.J. Hammarström, Annika Jenmalm Jensen, Lene Uhrbom, A.F. Maarten Altelaar, Sten Linnarsson, Per Uhlén, Lukas Trantirek, C. Theresa Vincent, Sven Nelander, Per Øyvind Enger, Michael Andäng

Cell death analysis

Funding

Swedish Childhood Cancer Foundation

Swedish Cancer Foundation

Swedish Research Council

Karolinska Institutet

Grant Agency of the Czech Republic

CEITEC 2020

Ministry of Education Youth and Sports

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Ministry of Education, Youths and Sports of the Czech Republic

National Programme for Sustainability II funds

Netherlands Organization for Scientific Research

Prime XS-Consortium

seventh framework EU

History

ARTICLE ABSTRACT

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.

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Keywords

Cell Signaling Cns Cancers Computational Methods Gene expression profiling Drug Discovery Technologies Screening strategies (assays and chemical libraries)Drug Mechanisms Cellular responses to anticancer drugs Proteomics Small Molecule Agents Stem Cell Biology

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