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dc.contributor.authorChidley, Christopheren_US
dc.contributor.authorTrauger, Sunia Aen_US
dc.contributor.authorBirsoy, Kıvançen_US
dc.contributor.authorO'Shea, Erin Ken_US
dc.date.accessioned2016-08-09T14:54:18Z
dc.date.issued2016en_US
dc.identifier.citationChidley, Christopher, Sunia A Trauger, Kıvanç Birsoy, and Erin K O'Shea. 2016. “The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine.” eLife 5 (1): e14601. doi:10.7554/eLife.14601. http://dx.doi.org/10.7554/eLife.14601.en
dc.identifier.issn2050-084Xen
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27822349
dc.description.abstractPhenotypic screens allow the identification of small molecules with promising anticancer activity, but the difficulty in characterizing the mechanism of action of these compounds in human cells often undermines their value as drug leads. Here, we used a loss-of-function genetic screen in human haploid KBM7 cells to discover the mechanism of action of the anticancer natural product ophiobolin A (OPA). We found that genetic inactivation of de novo synthesis of phosphatidylethanolamine (PE) mitigates OPA cytotoxicity by reducing cellular PE levels. OPA reacts with the ethanolamine head group of PE in human cells to form pyrrole-containing covalent cytotoxic adducts and these adducts lead to lipid bilayer destabilization. Our characterization of this unusual cytotoxicity mechanism, made possible by unbiased genetic screening in human cells, suggests that the selective antitumor activity displayed by OPA may be due to altered membrane PE levels in cancer cells. DOI: http://dx.doi.org/10.7554/eLife.14601.001en
dc.language.isoen_USen
dc.publishereLife Sciences Publications, Ltden
dc.relation.isversionofdoi:10.7554/eLife.14601en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942256/pdf/en
dash.licenseLAAen_US
dc.subjectchemical biologyen
dc.subjectmechanism of actionen
dc.subjectcytotoxicityen
dc.subjectcovalent modificationen
dc.subjectdrug developmenten
dc.subjectgenetic screenen
dc.subjectHumanen
dc.titleThe anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamineen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journaleLifeen
dash.depositing.authorTrauger, Sunia Aen_US
dc.date.available2016-08-09T14:54:18Z
dc.identifier.doi10.7554/eLife.14601*
dash.contributor.affiliatedO'Shea, Erin
dash.contributor.affiliatedTrauger, Sunia


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