Počet záznamů: 1
Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells
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SYSNO ASEP 0506804 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells Tvůrce(i) Šalovská, Barbora (UMG-J)
Janečková, H. (CZ)
Fabrik, I. (CZ)
Karlikova, R. (CZ)
Cechakova, L. (CZ)
Ondřej, M. (CZ)
Link, M. (CZ)
Friedecký, D. (CZ)
Tichý, A. (CZ)Celkový počet autorů 9 Číslo článku e0199349 Zdroj.dok. PLoS ONE. - : Public Library of Science - ISSN 1932-6203
Roč. 13, č. 7 (2018)Poč.str. 39 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova dna-damage response ; gamma-radiation ; mass-spectrometry ; oxidative stress ; leukemic-cells ; targeting atr ; hl-60 cells ; phosphorylation ; kinase ; mtor Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Cell biology Způsob publikování Open access Institucionální podpora UMG-J - RVO:68378050 UT WOS 000438457400007 DOI 10.1371/journal.pone.0199349 Anotace 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 mu M 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 mu M 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2020 Elektronická adresa https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199349
Počet záznamů: 1