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The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine
Phenotypic 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 haplo...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942256/ https://www.ncbi.nlm.nih.gov/pubmed/27403889 http://dx.doi.org/10.7554/eLife.14601 |
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author | Chidley, Christopher Trauger, Sunia A Birsoy, Kıvanç O'Shea, Erin K |
author_facet | Chidley, Christopher Trauger, Sunia A Birsoy, Kıvanç O'Shea, Erin K |
author_sort | Chidley, Christopher |
collection | PubMed |
description | Phenotypic 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.14601.001 |
format | Online Article Text |
id | pubmed-4942256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-49422562016-07-13 The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine Chidley, Christopher Trauger, Sunia A Birsoy, Kıvanç O'Shea, Erin K eLife Cancer Biology Phenotypic 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.14601.001 eLife Sciences Publications, Ltd 2016-07-12 /pmc/articles/PMC4942256/ /pubmed/27403889 http://dx.doi.org/10.7554/eLife.14601 Text en © 2016, Chidley et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Chidley, Christopher Trauger, Sunia A Birsoy, Kıvanç O'Shea, Erin K The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title | The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title_full | The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title_fullStr | The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title_full_unstemmed | The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title_short | The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine |
title_sort | anticancer natural product ophiobolin a induces cytotoxicity by covalent modification of phosphatidylethanolamine |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942256/ https://www.ncbi.nlm.nih.gov/pubmed/27403889 http://dx.doi.org/10.7554/eLife.14601 |
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