Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses.
Niklasson M*
(1, 2)
,
Maddalo G*
(3)
,
Sramkova Z*
(2, 4)
,
Mutlu E*
(5)
,
Wee S*
(2)
,
Sekyrova P
(2, 4)
,
Schmidt L
(1)
,
Fritz N
(6)
,
Dehnisch I
(7)
,
Grigorios Kyriatzis
(2)
,
Krafcikova M
(4)
,
Carson Bb
(2, 8)
,
Feenstra Jm
(2, 8)
,
Marinescu Vd
(1)
,
Segerman A
(1)
,
Haraldsson M
(7)
,
Gustavsson Al
(7)
,
Hammarström Lg
(7)
,
Jenmalm Jensen A
(7)
,
Uhrbom L
(1)
,
Altelaar Af
(3)
,
Linnarsson S
(7)
,
Uhlén P
(7)
,
Trantirek L
(4)
,
Vincent Ct
(2, 8)
,
Nelander S
(1)
,
Enger Pø
(5, 9)
,
Andäng M
(2, 4)
1
Uppsala University
2 Department of Physiology and Pharmacology Karolinska Institute
3 Department of Biomolecular Mass Spectrometry and Proteomics Group [Utrecht, The Netherlands]
4 CEITEC MU - Central European Institute of Technology [Brno]
5 Univ Bergen, Dept Biomed, Bergen, Norway
6 iDepartment of Materials and Engineering, Applied Materials Physics, Royal Institute of Technology
7 Karolinska Institutet [Stockholm]
8 Department of Physiology and Biophysics, Weill Cornell Medical College
9 Haukeland University Hospital
2 Department of Physiology and Pharmacology Karolinska Institute
3 Department of Biomolecular Mass Spectrometry and Proteomics Group [Utrecht, The Netherlands]
4 CEITEC MU - Central European Institute of Technology [Brno]
5 Univ Bergen, Dept Biomed, Bergen, Norway
6 iDepartment of Materials and Engineering, Applied Materials Physics, Royal Institute of Technology
7 Karolinska Institutet [Stockholm]
8 Department of Physiology and Biophysics, Weill Cornell Medical College
9 Haukeland University Hospital
Grigorios Kyriatzis
- Fonction : Auteur
- PersonId : 173459
- IdHAL : kyriatzisgr
Résumé
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.