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Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells
B. Šalovská, H. Janečková, I. Fabrik, R. Karlíková, L. Čecháková, M. Ondrej, M. Link, D. Friedecký, A. Tichý,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 2006
Free Medical Journals
od 2006
Public Library of Science (PLoS)
od 2006
PubMed Central
od 2006
Europe PubMed Central
od 2006
ProQuest Central
od 2006-12-01
Open Access Digital Library
od 2006-01-01
Open Access Digital Library
od 2006-10-01
Open Access Digital Library
od 2006-01-01
Medline Complete (EBSCOhost)
od 2008-01-01
Nursing & Allied Health Database (ProQuest)
od 2006-12-01
Health & Medicine (ProQuest)
od 2006-12-01
Public Health Database (ProQuest)
od 2006-12-01
ROAD: Directory of Open Access Scholarly Resources
od 2006
- MeSH
- aminokyselinové motivy MeSH
- ATM protein antagonisté a inhibitory MeSH
- biologické markery MeSH
- fosfoproteiny * chemie metabolismus MeSH
- fosforylace MeSH
- genová ontologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- kontrolní body buněčného cyklu účinky léků účinky záření MeSH
- lidé MeSH
- metabolom * MeSH
- metabolomika metody MeSH
- nádorové buněčné linie MeSH
- proteom * MeSH
- proteomika metody MeSH
- pyraziny farmakologie MeSH
- radiosenzibilizující látky farmakologie MeSH
- signální transdukce MeSH
- sulfony farmakologie MeSH
- tolerance záření účinky léků MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- výpočetní biologie metody MeSH
- záření gama MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Current anti-cancer strategy takes advantage of tumour specific abnormalities in DNA damage response to radio- or chemo-therapy. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of T-lymphocyte leukemic MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells. VE-821 radiosensitized MOLT-4 cells, and furthermore 10 μM VE-821 significantly affected proliferation of sham-irradiated MOLT-4 cells. We detected 623 differentially regulated phosphorylation sites. We revealed changes not only in DDR-related pathways and kinases, but also in pathways and kinases involved in maintaining cellular metabolism. Notably, we found downregulation of mTOR, the main regulator of cellular metabolism, which was most likely caused by an off-target effect of the inhibitor, and we propose that mTOR inhibition could be one of the factors contributing to the phenotype observed after treating MOLT-4 cells with 10 μM VE-821. In the metabolomic analysis, 206 intermediary metabolites were detected. The data indicated that VE-821 potentiated metabolic disruption induced by irradiation and affected the response to irradiation-induced oxidative stress. Upon irradiation, recovery of damaged deoxynucleotides might be affected by VE-821, hampering DNA repair by their deficiency. Taken together, this is the first study describing a complex scenario of cellular events that might be ATR-dependent or triggered by ATR inhibition in irradiated MOLT-4 cells. Data are available via ProteomeXchange with identifier PXD008925.
Citace poskytuje Crossref.org
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- $a Šalovská, Barbora $u Department of Radiobiology, Faculty of Military Health Sciences in Hradec Králové, University of Defence in Brno, Hradec Králové, Czech Republic. Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
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- $a Current anti-cancer strategy takes advantage of tumour specific abnormalities in DNA damage response to radio- or chemo-therapy. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of T-lymphocyte leukemic MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells. VE-821 radiosensitized MOLT-4 cells, and furthermore 10 μM VE-821 significantly affected proliferation of sham-irradiated MOLT-4 cells. We detected 623 differentially regulated phosphorylation sites. We revealed changes not only in DDR-related pathways and kinases, but also in pathways and kinases involved in maintaining cellular metabolism. Notably, we found downregulation of mTOR, the main regulator of cellular metabolism, which was most likely caused by an off-target effect of the inhibitor, and we propose that mTOR inhibition could be one of the factors contributing to the phenotype observed after treating MOLT-4 cells with 10 μM VE-821. In the metabolomic analysis, 206 intermediary metabolites were detected. The data indicated that VE-821 potentiated metabolic disruption induced by irradiation and affected the response to irradiation-induced oxidative stress. Upon irradiation, recovery of damaged deoxynucleotides might be affected by VE-821, hampering DNA repair by their deficiency. Taken together, this is the first study describing a complex scenario of cellular events that might be ATR-dependent or triggered by ATR inhibition in irradiated MOLT-4 cells. Data are available via ProteomeXchange with identifier PXD008925.
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