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Label-free target identification reveals oxidative DNA damage as the mechanism of a selective cytotoxic agent

DC Field Value Language
dc.contributor.authorPark, Hankum-
dc.contributor.authorPark, Seung Bum-
dc.date.accessioned2023-05-03T05:45:49Z-
dc.date.available2023-05-03T05:45:49Z-
dc.date.created2020-01-30-
dc.date.created2020-01-30-
dc.date.created2020-01-30-
dc.date.created2020-01-30-
dc.date.issued2019-03-
dc.identifier.citationChemical Science, Vol.10 No.12, pp.3449-3458-
dc.identifier.issn2041-6520-
dc.identifier.urihttps://hdl.handle.net/10371/191795-
dc.description.abstractPhenotypic screening can not only identify promising first-in-class drug candidates, but can also reveal potential therapeutic targets or neomorphic functions of known proteins. In this study, we identified target proteins of SB2001, a cytotoxic agent that acts specifically against HeLa human cervical cancer cells. Because SB2001 lacks chemical modification sites, label-free target identification methods including thermal stability shift-based fluorescence difference in two-dimensional gel electrophoresis (TS-FITGE) and thermal proteome profiling (TPP) were applied to characterize its mechanism of action. Owing to their differences, the two label-free target identification methods uncovered complementary target candidates. Candidates from both methods were prioritized according to their selective lethality upon the knockdown of those genes in HeLa cells, compared to CaSki cells which were used as a negative control cell line from the human cervix. LTA4H was identified only by TS-FITGE, but not by TPP, because only one isoform was stabilized by SB2001. Furthermore, it was implied that a non-canonical function of LTA4H was involved in the SB2001 activity. MTH1 was identified by both TS-FITGE and TPP, and SB2001 inhibited the function of MTH1 in hydrolyzing oxidized nucleotides. Compared to CaSki cells, HeLa cells displayed downregulated DNA mismatch repair pathways, which made HeLa cells more susceptible to the oxidative stress caused by SB2001, resulting in increased 8-oxoG concentrations, DNA damage, and subsequent cell death.-
dc.language영어-
dc.publisherRoyal Society of Chemistry-
dc.titleLabel-free target identification reveals oxidative DNA damage as the mechanism of a selective cytotoxic agent-
dc.typeArticle-
dc.identifier.doi10.1039/c8sc05465g-
dc.citation.journaltitleChemical Science-
dc.identifier.wosid000463759100028-
dc.identifier.scopusid2-s2.0-85063349248-
dc.citation.endpage3458-
dc.citation.number12-
dc.citation.startpage3449-
dc.citation.volume10-
dc.description.isOpenAccessY-
dc.contributor.affiliatedAuthorPark, Hankum-
dc.contributor.affiliatedAuthorPark, Seung Bum-
dc.type.docTypeArticle-
dc.description.journalClass1-
dc.subject.keywordPlusMISMATCH REPAIR-
dc.subject.keywordPlusTUMOR-CELLS-
dc.subject.keywordPlusLEUKOTRIENE-A4 HYDROLASE-
dc.subject.keywordPlusMUTAGENIC SUBSTRATE-
dc.subject.keywordPlusDRUG DISCOVERY-
dc.subject.keywordPlusCANCER-
dc.subject.keywordPlusMTH1-
dc.subject.keywordPlusHYDROLYZES-
dc.subject.keywordPlusBIOLOGY-
dc.subject.keywordPlusPOTENT-
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  • School of Dentistry
  • Department of Dentistry
Research Area Metaproteomics, Molecular Interactions, Pathogenic Microbial Proteins, 메타단백체학, 병원성 미생물 단백질, 분자 상호작용

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