The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH

Jo Ão Azevedo-Silva, Odília Queirós, Ana Ribeiro, Fátima Baltazar, Ko H. Young, Peter L. Pedersen, Ana Pretoand, Margarida Casal

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Abstract

Although the anti-cancer properties of 3BP (3-bromopyruvate) have been described previously, its selectivity for cancer cells still needs to be explained [Ko et al. (2001) Cancer Lett. 173, 83-91]. In the present study, we characterized the kinetic parameters of radiolabelled [14 C] 3BP uptake in three breast cancer cell lines that display different levels of resistance to 3BP: ZR-75-1< MCF-7 < SK-BR-3. At pH 6.0, the affinity of cancer cells for 3BP transport correlates with their sensitivity, a pattern that does not occur at pH 7.4. In the three cell lines, the uptake of 3BP is dependent on the protonmotive force and is decreased by MCTs (monocarboxylate transporters) inhibitors. In the SK-BR-3 cell line, a sodium-dependent transport also occurs.Butyrate promotes the localization of MCT-1 at the plasma membrane and increases the level of MCT-4 expression, leading to a higher sensitivity for 3BP. In the present study, we demonstrate that this phenotype is accompanied by an increase in affinity for 3BP uptake. Our results confirm the role of MCTs, especially MCT-1, in 3BP uptake and the importance of cluster of differentiation (CD) 147 glycosylation in this process.We find that the affinity for 3BP transport is higher when the extracellularmilieu is acidic. This is a typical phenotype of tumour microenvironment and explains the lack of secondary effects of 3BP already described in in vivo studies [Ko et al. (2004) Biochem. Biophys. Res. Commun. 324, 269-275].

Original languageEnglish (US)
Pages (from-to)247-258
Number of pages12
JournalBiochemical Journal
Volume467
Issue number2
DOIs
StatePublished - Apr 15 2015

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Keywords

  • 3-bromopyruvate
  • Cluster of differentiation (CD) 147
  • Extracellular acid pH
  • Lactate
  • Monocarboxylate transporter
  • Tumour microenvironment

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Azevedo-Silva, J. Ã., Queirós, O., Ribeiro, A., Baltazar, F., Young, K. H., Pedersen, P. L., Pretoand, A., & Casal, M. (2015). The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH. Biochemical Journal, 467(2), 247-258. https://doi.org/10.1042/BJ20140921