title: Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses.
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 KCachannels 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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Niklasson
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Maddalo
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Sramkova
authors.affiliation: Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Ercan
authors.initials: E
authors.lastname: Mutlu
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Shimei
authors.initials: S
authors.lastname: Wee
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Sekyrova
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Linnéa
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fritz
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ivar
authors.initials: I
authors.lastname: Dehnisch
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gregorios
authors.initials: G
authors.lastname: Kyriatzis
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Krafcikova
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
authors.forename: Brittany B
authors.initials: BB
authors.lastname: Carson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Feenstra
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Voichita D
authors.initials: VD
authors.lastname: Marinescu
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Segerman
authors.affiliation: Chemical Biology Consortium Sweden, Division of Translational Medicine and Chemical Biology, Department of Medical Chemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Haraldsson
authors.affiliation: Chemical Biology Consortium Sweden, Division of Translational Medicine and Chemical Biology, Department of Medical Chemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Gustavsson
authors.affiliation: Chemical Biology Consortium Sweden, Division of Translational Medicine and Chemical Biology, Department of Medical Chemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars G J
authors.initials: LG
authors.lastname: Hammarström
authors.affiliation: Chemical Biology Consortium Sweden, Division of Translational Medicine and Chemical Biology, Department of Medical Chemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Jenmalm Jensen
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: A F Maarten
authors.initials: AF
authors.lastname: Altelaar
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
authors.affiliation: Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Lukas
authors.initials: L
authors.lastname: Trantirek
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
authors.forename: C Theresa
authors.initials: CT
authors.lastname: Vincent
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.|Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Øyvind
authors.initials: PØ
authors.lastname: Enger
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. michael.andang@ki.se.|Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: Michael
authors.initials: M
authors.lastname: Andäng
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D016923:Cell Death; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009183:Mycotoxins / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000473:pathology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D040901:Proteomics; D012964:Sodium / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000596:Amino Acids; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009183:Mycotoxins; D024681:Potassium Channels, Calcium-Activated; C003626:tremortin; D012964:Sodium; C054074:niguldipine