High-Throughput Screening for Growth Inhibitors Using a Yeast Model of Familial Paraganglioma

Bancos, Irina; Bida, John Paul; Tian, Defeng; Bundrick, Mary; John, Kristen; Holte, Molly Nelson; Her, Yeng F.; Evans, Debra; Saenz, Dyana T.; Poeschla, Eric M.; Hook, Derek; Georg, Gunda; Maher III, L. James
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
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.


Related Articles

  • L157X nonsense mutation of the succinate dehydrogenase subunit B gene in a Japanese patient with right paraaortic paraganglioma. Sato, Haruhiro; Kanai, Genta; Hirabayshi, Kenichi; Kajiwara, Hiroshi; Itoh, Johbu; Osamura, Robert Yoshiyuki // Endocrine (1355008X);Aug2010, Vol. 38 Issue 1, p18 

    Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal...

  • Early Presentation of Familial Paraganglioma with SDHB Mutation in a 13 year old Child and its Mother. Santiago, Angela H.; Campbell, Brendan T.; Estrada, D. Elizabeth // Journal of Pediatric Endocrinology & Metabolism;Apr2010, Vol. 23 Issue 4, p419 

    The article discusses the clinical case of a 13-year-old boy who was diagnosed with familial paraganglioma with succinate dehydrogenase complex (SDH). The mother of the boy also had thoracic paraganglioma, and both of them presented a mutation in exon 4 of the SDHB gene. The study suggested...

  • Molecular characterisation of a common SDHB deletion in paraganglioma patients. Cascón, A.; Landa, Í; López-Jiménez, E.; Díez-Hernández, A.; Buchta, M.; Montero-Conde, C.; Leskelä, S.; Leandro-García, L. J.; Letón, R.; Rodríguez-Antona, C.; Eng, C.; Neumann, H. P. H.; Robledo, M. // Journal of Medical Genetics;Apr2008, Vol. 45 Issue 4, p233 

    Background: Hereditary susceptibility to familial paraganglioma syndromes is mainly due to mutations in one of six genes, including three of the four genes encoding the subunits of the mitochondrial succinate dehydrogenase complex II. Although prevalence, penetrance and clinical characteristics...

  • CORRECTIONS.  // Annals of Internal Medicine;11/6/2012, Vol. 157 Issue 9, p680 

    A correction to the article "Long-Delayed Localization of a Cardiac Functional Paraganglioma With SDHC Mutation," that was published in the previous issue of the periodical is presented.

  • Malignant paragangliomas with succinate dehydrogenase subunit B mutation in a 13-year old child treated successfully with surgery and 131-I-MIBG. Chi Kwan Jasmine Chow; PW Yau; CP Wong; Angel Chan; WM But // International Journal of Pediatric Endocrinology;2013, Vol. 2013 Issue Suppl 1, p1 

    An abstract of the study "Malignant Paragangliomas With Succinate Dehydrogenase Subunit B Mutation in a 13-Year-Old Child Treated Successfully With Surgery and 131-I-MIBG" by Chi Kwan Jasmine Chow et al is presented.

  • Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism. Starker, Lee; Delgado-Verdugo, Alberto; Udelsman, Robert; Björklund, Peyman; Carling, Tobias // Endocrine (1355008X);Dec2010, Vol. 38 Issue 3, p397 

    To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors...

  • A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21WAF1/Cip1 Induction and Mitochondrial Dysfunction. Millán-Uclés, África; Díaz-Castro, Blanca; García-Flores, Paula; Báez, Alicia; Pérez-Simón, José Antonio; López-Barneo, José; Piruat, José I. // PLoS ONE;Jan2014, Vol. 9 Issue 1, p1 

    Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of...

  • Mitochondrial and Nuclear Genes of Mitochondrial Components in Cancer. Kirches, E. // Current Genomics;Jun2009, Vol. 10 Issue 4, p281 

    Although the observation of aerobic glycolysis of tumor cells by Otto v. Warburg had demonstrated abnormalities of mitochondrial energy metabolism in cancer decades ago, there was no clear evidence for a functional role of mutant mitochondrial proteins in cancer development until the early years...

  • Diagnostic performance of F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis. Treglia, Giorgio; Cocciolillo, Fabrizio; Waure, Chiara; Nardo, Francesco; Gualano, Maria; Castaldi, Paola; Rufini, Vittoria; Giordano, Alessandro // European Journal of Nuclear Medicine & Molecular Imaging;Jul2012, Vol. 39 Issue 7, p1144 

    Purpose: The aim of this study was to systematically review and conduct a meta-analysis of published data about the diagnostic performance of F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) in patients with paraganglioma (PG). Methods: A comprehensive computer literature...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics