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

J 2017

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

NIKLASSON, M., G. MADDALO, Zuzana ŠRÁMKOVÁ, E. MUTLU, S. WEE et. al.

Basic information

Original name

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

Authors

NIKLASSON, M. (752 Sweden), G. MADDALO (528 Netherlands), Zuzana ŠRÁMKOVÁ (703 Slovakia, belonging to the institution), E. MUTLU (578 Norway), S. WEE (752 Sweden), Petra SEKYROVÁ (203 Czech Republic, belonging to the institution), L. SCHMIDT (752 Sweden), N. FRITZ (752 Sweden), I. DEHNISCH (752 Sweden), G. KYRIATZIS (752 Sweden), Michaela KRAFČÍKOVÁ (703 Slovakia, belonging to the institution), B.B. CARSON (840 United States of America), J.M. FEENSTRA (752 Sweden), V.D. MARINESCU (752 Sweden), A. SEGERMAN (752 Sweden), M. HARALDSSON (752 Sweden), A.L. GUSTAVSSON (752 Sweden), L.G.J. HAMMARSTROM (752 Sweden), A.J. JENSEN (752 Sweden), L. UHRBOM (752 Sweden), A.F.M. ALTELAAR (528 Netherlands), S. LINNARSSON (752 Sweden), P. UHLEN (752 Sweden), Lukáš TRANTÍREK (203 Czech Republic, guarantor, belonging to the institution), C.T. VINCENT (752 Sweden), S. NELANDER (752 Sweden), P.O. ENGER (752 Sweden) and Michael ANDÄNG (752 Sweden, belonging to the institution)

Edition

Cancer Research, PHILADELPHIA, AMER ASSOC CANCER RESEARCH, 2017, 0008-5472

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 9.130

RIV identification code

RIV/00216224:14740/17:00095470

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1158/0008-5472.CAN-16-2274

UT WoS

000398262400020

Keywords in English

TUMOR-INITIATING CELLS; CANCER STEM-CELLS; T-TYPE; HUMAN GLIOBLASTOMA; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; HIGH-THROUGHPUT; INHIBITION; CULTURE; IDENTIFICATION

Abstract

V originále

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.

Links

GA15-20818S, research and development project

Name: Cílená terapie proti rezistentím kmenovým buňkám gliomového nádoru - kontrola přísunu živin pomocí iontových kanálů

Investor: Czech Science Foundation

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

NIKLASSON, M., G. MADDALO, Zuzana ŠRÁMKOVÁ, E. MUTLU, S. WEE, Petra SEKYROVÁ, L. SCHMIDT, N. FRITZ, I. DEHNISCH, G. KYRIATZIS, Michaela KRAFČÍKOVÁ, B.B. CARSON, J.M. FEENSTRA, V.D. MARINESCU, A. SEGERMAN, M. HARALDSSON, A.L. GUSTAVSSON, L.G.J. HAMMARSTROM, A.J. JENSEN, L. UHRBOM, A.F.M. ALTELAAR, S. LINNARSSON, P. UHLEN, Lukáš TRANTÍREK, C.T. VINCENT, S. NELANDER, P.O. ENGER and Michael ANDÄNG. Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses. Cancer Research. PHILADELPHIA: AMER ASSOC CANCER RESEARCH, 2017, vol. 77, No 7, p. 1741-1752. ISSN 0008-5472. Available from: https://dx.doi.org/10.1158/0008-5472.CAN-16-2274.

@article{1406729,
   author = {Niklasson, M. and Maddalo, G. and Šrámková, Zuzana and Mutlu, E. and Wee, S. and Sekyrová, Petra and Schmidt, L. and Fritz, N. and Dehnisch, I. and Kyriatzis, G. and Krafčíková, Michaela and Carson, B.B. and Feenstra, J.M. and Marinescu, V.D. and Segerman, A. and Haraldsson, M. and Gustavsson, A.L. and Hammarstrom, L.G.J. and Jensen, A.J. and Uhrbom, L. and Altelaar, A.F.M. and Linnarsson, S. and Uhlen, P. and Trantírek, Lukáš and Vincent, C.T. and Nelander, S. and Enger, P.O. and Andäng, Michael},
   article_location = {PHILADELPHIA},
   article_number = {7},
   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},
   language = {eng},
   issn = {0008-5472},
   journal = {Cancer Research},
   title = {Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses},
   url = {http://cancerres.aacrjournals.org/content/77/7/1741.short},
   volume = {77},
   year = {2017}
}

TY  - JOUR
ID  - 1406729
AU  - 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
PY  - 2017
TI  - Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
JF  - Cancer Research
VL  - 77
IS  - 7
SP  - 1741-1752
EP  - 1741-1752
PB  - AMER ASSOC CANCER RESEARCH
SN  - 00085472
KW  - TUMOR-INITIATING CELLS
KW  - CANCER STEM-CELLS
KW  - T-TYPE
KW  - HUMAN GLIOBLASTOMA
KW  - MULTIDRUG-RESISTANCE
KW  - GENE-EXPRESSION
KW  - HIGH-THROUGHPUT
KW  - INHIBITION
KW  - CULTURE
KW  - IDENTIFICATION
UR  - http://cancerres.aacrjournals.org/content/77/7/1741.short
L2  - http://cancerres.aacrjournals.org/content/77/7/1741.short
N2  - 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.
ER  -

NIKLASSON, M., G. MADDALO, Zuzana ŠRÁMKOVÁ, E. MUTLU, S. WEE, Petra SEKYROVÁ, L. SCHMIDT, N. FRITZ, I. DEHNISCH, G. KYRIATZIS, Michaela KRAFČÍKOVÁ, B.B. CARSON, J.M. FEENSTRA, V.D. MARINESCU, A. SEGERMAN, M. HARALDSSON, A.L. GUSTAVSSON, L.G.J. HAMMARSTROM, A.J. JENSEN, L. UHRBOM, A.F.M. ALTELAAR, S. LINNARSSON, P. UHLEN, Lukáš TRANTÍREK, C.T. VINCENT, S. NELANDER, P.O. ENGER and Michael ANDÄNG. Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses. \textit{Cancer Research}. PHILADELPHIA: AMER ASSOC CANCER RESEARCH, 2017, vol.~77, No~7, p.~1741-1752. ISSN~0008-5472. Available from: https://dx.doi.org/10.1158/0008-5472.CAN-16-2274.

Detailed Information on Publication Record