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Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy

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Abstract

The small molecule 3-bromopyruvate (3BP), is an anticancer molecule that acts by hindering glycolysis and mitochondrial function leading to energy depletion and consequently, to cell death. In this work we have focused on understanding how the glycolytic inhibition affects cancer cell structural features. We showed that 3BP leads to a drastic decrease in the levels of β-actin and α-tubulin followed by disorganization and shrinkage of the cytoskeleton in breast cancer cells. 3BP inhibits cell migration and colony formation independently of the activity of metalloproteinases. To disclose if these structural alterations occurred prior to 3BP toxic effect, non-toxic concentrations of 3BP were used and we could observe that 3BP was able to inhibit energy production and induce loss of β-actin and α-tubulin proteins. This was accompanied with alterations in cytoskeleton organization and an increase in E-cadherin levels which may indicate a decrease in cancer cells aggressiveness. In this study we demonstrate that 3BP glycolytic inhibition of breast cancer cells is accompanied by cytoskeleton disruption and consequently loss of migration ability, suggesting that 3BP can potentially be explored for metastatic breast cancer therapy.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work is dedicated to the memory of Professor André Goffeau, a visionary scientist who encouraged us to study 3-bromopyruvate for cancer research. This work was supported by the strategic programme UID/BIA/04050/2019 funded by Portuguese funds through the FCT I.P., João Azevedo-Silva received a fellowship from the Portuguese government from the FCT through FSE (Fundo Social Europeu) and POPH (Programa Operacional Potencial Humano) [grant number SFRH/BD/76038/2011]. We are grateful to Joana Paredes (I3S, Portugal) for the gently donation of E-cadherin antibody used in this work.

Funding

This work was supported by the strategic programme UID/BIA/04050/2019 funded by Portuguese funds through the FCT I.P., João Azevedo-Silva received a fellowship from the Portuguese government from the FCT through FSE (Fundo Social Europeu) and POPH (Programa Operacional Potencial Humano) [Grant Number SFRH/BD/76038/2011].

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Author notes

  1. A. Preto and M. Casal: senior authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Centre of Molecular and Environmental Biology (CBMA), University of Minho, Portugal, Campus de Gualtar, 4710-057, Braga, Portugal

    J. Azevedo-Silva, A. Almeida, A. Preto & M. Casal

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal

    D. Tavares-Valente & F. Baltazar

  3. Department of Sciences, IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, CESPU, CRL, University Institute of Health Sciences (IUCS), Gandra, Portugal

    D. Tavares-Valente & O. Queirós

  4. KoDiscovery, LLC, University of Maryland BioPark, Suites 502 E & F, 801 West Baltimore St., Baltimore, MD, 21201, USA

    Y. H. Ko

  5. Departments of Biological Chemistry and Oncology, Member at Large, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, 21205-2185, USA

    P. L. Pedersen

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  1. J. Azevedo-Silva
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Contributions

JAS carried out the Western-blots, fluorescence microscopy, colony formation assay, wound-healing assay and metalloproteinase activity. DV, OQ and FB carried out the metabolic analysis. AA carried out western-blots and confocal microscopy. YK and PL had verified the results and participated in the critical and conceptual analysis of the study. JAS, AP and MC conceived the study and participated in its design and implementation. JAS wrote the manuscript supervised by AP and MC. All authors read and approved the final manuscript.

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Correspondence to J. Azevedo-Silva or M. Casal.

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Azevedo-Silva, J., Tavares-Valente, D., Almeida, A. et al. Cytoskeleton disruption by the metabolic inhibitor 3-bromopyruvate: implications in cancer therapy. Med Oncol 39, 121 (2022). https://doi.org/10.1007/s12032-022-01712-0

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