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Oncotarget. 2016 Mar 1;7(9):10153-73. doi: 10.18632/oncotarget.7174.

Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate.

Author information

1
Department of Genetics, Institute of Genetics and Microbiology, University of Wrocław, Wrocław, Poland.
2
KoDiscovery LLC, UM BioPark, Innovation Center, Baltimore, MD, USA.
3
Departments of Biological Chemistry and Oncology, Sydney Kimmel Comprehensive Cancer Center and Center for Obesity Research and Metabolism, John Hopkins University School of Medicine, Baltimore, MD, USA.
4
Unité de Biochimie Physiologique, Institut des Sciences de la Vie, Université Catholique de Louvain-la-Neuve, Louvain-la-Neuve, Belgium.

Abstract

In this study the detailed characteristic of the anti-cancer agent 3-bromopyruvate (3-BP) activity in the yeast Saccharomyces cerevisiae model is described, with the emphasis on its influence on energetic metabolism of the cell. It shows that 3-BP toxicity in yeast is strain-dependent and influenced by the glucose-repression system. Its toxic effect is mainly due to the rapid depletion of intracellular ATP. Moreover, lack of the Whi2p phosphatase results in strongly increased sensitivity of yeast cells to 3-BP, possibly due to the non-functional system of mitophagy of damaged mitochondria through the Ras-cAMP-PKA pathway. Single deletions of genes encoding glycolytic enzymes, the TCA cycle enzymes and mitochondrial carriers result in multiple effects after 3-BP treatment. However, it can be concluded that activity of the pentose phosphate pathway is necessary to prevent the toxicity of 3-BP, probably due to the fact that large amounts of NADPH are produced by this pathway, ensuring the reducing force needed for glutathione reduction, crucial to cope with the oxidative stress. Moreover, single deletions of genes encoding the TCA cycle enzymes and mitochondrial carriers generally cause sensitivity to 3-BP, while totally inactive mitochondrial respiration in the rho0 mutant resulted in increased resistance to 3-BP.

KEYWORDS:

3-bromopyruvate (3-BP); Saccharomyces cerevisiae; Whi2; energetic metabolism; genomic screen

PMID:
26862728
PMCID:
PMC4891110
DOI:
10.18632/oncotarget.7174
[Indexed for MEDLINE]
Free PMC Article

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