High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.

Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic...

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Autores principales:	Irina Bancos, John Paul Bida, Defeng Tian, Mary Bundrick, Kristen John, Molly Nelson Holte, Yeng F Her, Debra Evans, Dyana T Saenz, Eric M Poeschla, Derek Hook, Gunda Georg, L James Maher
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f59d566d9d2d4a60a0109f1d98d39a5c
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spelling	oai:doaj.org-article:f59d566d9d2d4a60a0109f1d98d39a5c2021-11-18T07:56:24ZHigh-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.1932-620310.1371/journal.pone.0056827https://doaj.org/article/f59d566d9d2d4a60a0109f1d98d39a5c2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23451094/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.Irina BancosJohn Paul BidaDefeng TianMary BundrickKristen JohnMolly Nelson HolteYeng F HerDebra EvansDyana T SaenzEric M PoeschlaDerek HookGunda GeorgL James MaherPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e56827 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Irina Bancos John Paul Bida Defeng Tian Mary Bundrick Kristen John Molly Nelson Holte Yeng F Her Debra Evans Dyana T Saenz Eric M Poeschla Derek Hook Gunda Georg L James Maher High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
description	Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.
format	article
author	Irina Bancos John Paul Bida Defeng Tian Mary Bundrick Kristen John Molly Nelson Holte Yeng F Her Debra Evans Dyana T Saenz Eric M Poeschla Derek Hook Gunda Georg L James Maher
author_facet	Irina Bancos John Paul Bida Defeng Tian Mary Bundrick Kristen John Molly Nelson Holte Yeng F Her Debra Evans Dyana T Saenz Eric M Poeschla Derek Hook Gunda Georg L James Maher
author_sort	Irina Bancos
title	High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
title_short	High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
title_full	High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
title_fullStr	High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
title_full_unstemmed	High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
title_sort	high-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f59d566d9d2d4a60a0109f1d98d39a5c
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High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.

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