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

Paweł Lis, Paweł Jurkiewicz, Magdalena Cal-Bakowska, Young H. Ko, Peter L. Pedersen, Andre Goffeau, Stanisław Ułaszewski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)10153-10173
Number of pages21
JournalOncotarget
Volume7
Issue number9
DOIs
StatePublished - 2016

Keywords

  • 3-bromopyruvate (3-BP)
  • Energetic metabolism
  • Genomic screen
  • Saccharomyces cerevisiae
  • Whi2

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Lis, P., Jurkiewicz, P., Cal-Bakowska, M., Ko, Y. H., Pedersen, P. L., Goffeau, A., & Ułaszewski, S. (2016). Screening the yeast genome for energetic metabolism pathways involved in a phenotypic response to the anti-cancer agent 3-bromopyruvate. Oncotarget, 7(9), 10153-10173. https://doi.org/10.18632/oncotarget.7174