Dataset Information

MOLT-4 radiosensitization by VE-821

ABSTRACT: DNA damage induction by either radio- or chemo-therapy has been the most widely used approach in cancer therapy, exploiting the genomic instability of cancer cells. A promising strategy takes advantage of tumour specific abnormalities in DNA damage response. 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 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, T Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Barbora Salovska

LAB HEAD: Aleš Tichý

PROVIDER: PXD008925 | Pride | 2018-07-16

REPOSITORIES: Pride

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Publications

Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells.

Šalovská Barbora B Janečková Hana H Fabrik Ivo I Karlíková Radana R Čecháková Lucie L Ondrej Martin M Link Marek M Friedecký David D Tichý Aleš A

PloS one 20180712 7

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. ...[more]

PMID: 30001349

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Project description:Phosphorylation is a regulatory mechanism by which intracellular apicomplexan parasites control the process of invading and modifying host cells. However, the sporulated oocysts’ phosphoprotein repertoires between virulent and avirulent strains of Toxoplasma gondii and the underlying mechanisms contributing to virulence is still a mystery. A quantitative analysis of the sporulated oocysts’ phosphoproteome profile of T. gondii virulent and avirulent strains belonging to different genotypes was conducted to reveal phosphoprotein expression patterns that contribute to the virulence of a particular phenotype. Phosphopeptides from the sporulated oocysts of the virulent strain PYS (Chinese ToxoDB#9) and the avirulent strain type II (PRU strain) were enriched by titanium dioxide (TiO2) affinity chromatography and quantified using iBT technology. A total of 10,645 unique phosphopeptides, 8,181 nonredundant phosphorylation sites and 2,792 phosphoproteins were identified. The quantitative analysis identified 4,129 differentially expressed phosphopeptides (DEPs) between sporulated oocysts of the PYS strain and PRU strain (|log1.5 fold change| > 1 and P < 0.05), including 2,485 upregulated and 1,644 downregulated phosphopeptides. Motif analysis identified 24 motifs from the upregulated phosphorylated peptides including 22 serine motifs and two threonine motifs (TPE and TP), and 15 motifs from the downregulated phosphorylated peptides including 12 serine motifs and three threonine motifs (TP, RxxT and KxxT) in PYS strain when comparing PYS/PRU. Several kinases were consistent with motifs of overrepresented phosphopeptides, such as PKA, PKG, CKII, IKK, MAPK, EGFR, INSR, Jak, Syk, Src, Ab1. GO analysis, KEGG pathway analysis and STRING analysis revealed differentially expressed phosphoproteins (DEPs) exhibiting significant functional properties. Kinase associated network analysis showed that AGC kinase had the greatest connected peptides. Our findings reveal significant difference in phosphopeptides of sporulated oocysts between virulent and avirulent T. gondii strains, which provides solid foundation for further exploring the mechanisms contributing to the virulence of T. gondii.

Dataset Information

MOLT-4 radiosensitization by VE-821

Publications

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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