Selective elimination of neuroblastoma cells by synergistic
effect of Akt kinase inhibitor and tetrathiomolybdate

J 2017

Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate

NAVRÁTILOVÁ, Jarmila, Martina KARASOVÁ, Martina KOHUTKOVÁ LÁNOVÁ, Ludmila JIRÁKOVÁ, Zuzana BUDKOVÁ et. al.

Základní údaje

Originální název

Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate

Autoři

NAVRÁTILOVÁ, Jarmila (203 Česká republika, domácí), Martina KARASOVÁ (203 Česká republika, domácí), Martina KOHUTKOVÁ LÁNOVÁ (203 Česká republika, domácí), Ludmila JIRÁKOVÁ (203 Česká republika, domácí), Zuzana BUDKOVÁ (203 Česká republika, domácí), Jiří PACHERNÍK (203 Česká republika, domácí), Jan ŠMARDA (203 Česká republika, domácí) a Petr BENEŠ (203 Česká republika, garant, domácí)

Vydání

Journal of Cellular and Molecular Medicine, Hoboken, NJ USA, Wiley, 2017, 1582-4934

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 4.302

Kód RIV

RIV/00216224:14310/17:00097304

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1111/jcmm.13106

UT WoS

000408320500018

Klíčová slova anglicky

neuroblastoma; tetrathiomolybdate; Akt kinase; cell viability; glycolysis; exygen consumtion; metabolic plasticity

Štítky

NZ, proteomics, rivok

Změněno: 11. 4. 2018 21:31, Ing. Nicole Zrilić

Anotace

V originále

Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase. It was oxidative phosphorylation that maintained intracellular level of ATP and proliferative capacity of these cells. The oxidative phosphorylation inhibitors (rotenone, tetrathiomolybdate) synergized with inhibitor of the Akt kinase/glucose uptake in down-regulation of both viability of neuroblastoma cells and clonogenic potential of cells forming neuroblastoma spheroids. Interestingly, tetrathiomolybdate acted as highly specific inhibitor of oxygen consumption and activator of lactate production in neuroblastoma cells, but not in normal fibroblasts and neuronal cells. Moreover, the reducing effect of tetrathiomolybdate on cell viability and the level of ATP in the cells with inhibited Akt kinase/glucose uptake was also selective for neuroblastoma cells. Therefore, efficient elimination of neuroblastoma cells requires inhibition of both glucose uptake/Akt kinase and oxidative phosphorylation activities. The use of tetrathiomolybdate as a mitochondrial inhibitor contributes to selectivity of this combined treatment, preferentially targeting neuroblastoma cells.

Návaznosti

MUNI/A/0967/2015, interní kód MU

Název: Podpora výzkumné činnosti studentů molekulární biologie a genetiky 4 (Akronym: MBG4)

Investor: Masarykova univerzita, Podpora výzkumné činnosti studentů molekulární biologie a genetiky 4, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

Přiložené soubory

Citovat

NAVRÁTILOVÁ, Jarmila, Martina KARASOVÁ, Martina KOHUTKOVÁ LÁNOVÁ, Ludmila JIRÁKOVÁ, Zuzana BUDKOVÁ, Jiří PACHERNÍK, Jan ŠMARDA a Petr BENEŠ. Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate. Journal of Cellular and Molecular Medicine. Hoboken, NJ USA: Wiley, 2017, roč. 21, č. 9, s. 1859-1869. ISSN 1582-4934. Dostupné z: https://dx.doi.org/10.1111/jcmm.13106.

@article{1386680,
   author = {Navrátilová, Jarmila and Karasová, Martina and Kohutková Lánová, Martina and Jiráková, Ludmila and Budková, Zuzana and Pacherník, Jiří and Šmarda, Jan and Beneš, Petr},
   article_location = {Hoboken, NJ USA},
   article_number = {9},
   doi = {http://dx.doi.org/10.1111/jcmm.13106},
   keywords = {neuroblastoma; tetrathiomolybdate; Akt kinase; cell viability; glycolysis; exygen consumtion; metabolic plasticity},
   language = {eng},
   issn = {1582-4934},
   journal = {Journal of Cellular and Molecular Medicine},
   title = {Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate},
   volume = {21},
   year = {2017}
}

TY  - JOUR
ID  - 1386680
AU  - Navrátilová, Jarmila - Karasová, Martina - Kohutková Lánová, Martina - Jiráková, Ludmila - Budková, Zuzana - Pacherník, Jiří - Šmarda, Jan - Beneš, Petr
PY  - 2017
TI  - Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate
JF  - Journal of Cellular and Molecular Medicine
VL  - 21
IS  - 9
SP  - 1859-1869
EP  - 1859-1869
PB  - Wiley
SN  - 15824934
KW  - neuroblastoma
KW  - tetrathiomolybdate
KW  - Akt kinase
KW  - cell viability
KW  - glycolysis
KW  - exygen consumtion
KW  - metabolic plasticity
N2  - Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase. It was oxidative phosphorylation that maintained intracellular level of ATP and proliferative capacity of these cells. The oxidative phosphorylation inhibitors (rotenone, tetrathiomolybdate) synergized with inhibitor of the Akt kinase/glucose uptake in down-regulation of both viability of neuroblastoma cells and clonogenic potential of cells forming neuroblastoma spheroids. Interestingly, tetrathiomolybdate acted as highly specific inhibitor of oxygen consumption and activator of lactate production in neuroblastoma cells, but not in normal fibroblasts and neuronal cells. Moreover, the reducing effect of tetrathiomolybdate on cell viability and the level of ATP in the cells with inhibited Akt kinase/glucose uptake was also selective for neuroblastoma cells. Therefore, efficient elimination of neuroblastoma cells requires inhibition of both glucose uptake/Akt kinase and oxidative phosphorylation activities. The use of tetrathiomolybdate as a mitochondrial inhibitor contributes to selectivity of this combined treatment, preferentially targeting neuroblastoma cells.
ER  -

NAVRÁTILOVÁ, Jarmila, Martina KARASOVÁ, Martina KOHUTKOVÁ LÁNOVÁ, Ludmila JIRÁKOVÁ, Zuzana BUDKOVÁ, Jiří PACHERNÍK, Jan ŠMARDA a Petr BENEŠ. Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate. \textit{Journal of Cellular and Molecular Medicine}. Hoboken, NJ USA: Wiley, 2017, roč.~21, č.~9, s.~1859-1869. ISSN~1582-4934. Dostupné z: https://dx.doi.org/10.1111/jcmm.13106.

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