Publication details

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

Authors

NIKLASSON M. MADDALO G. ŠRÁMKOVÁ Zuzana MUTLU E. WEE S. SEKYROVÁ Petra SCHMIDT L. FRITZ N. DEHNISCH I. KYRIATZIS G. KRAFČÍKOVÁ Michaela CARSON B.B. FEENSTRA J.M. MARINESCU V.D. SEGERMAN A. HARALDSSON M. GUSTAVSSON A.L. HAMMARSTROM L.G.J. JENSEN A.J. UHRBOM L. ALTELAAR A.F.M. LINNARSSON S. UHLEN P. TRANTÍREK Lukáš VINCENT C.T. NELANDER S. ENGER P.O. ANDÄNG Michael

Year of publication 2017
Type Article in Periodical
Magazine / Source Cancer Research
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://cancerres.aacrjournals.org/content/77/7/1741.short
Doi http://dx.doi.org/10.1158/0008-5472.CAN-16-2274
Keywords TUMOR-INITIATING CELLS; CANCER STEM-CELLS; T-TYPE; HUMAN GLIOBLASTOMA; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; HIGH-THROUGHPUT; INHIBITION; CULTURE; IDENTIFICATION
Description 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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