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Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

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Abstract

The main aim of this study was to investigate a possible functional connection between sigma-1 receptors and voltage-gated sodium channels (VGSCs) in human breast cancer cells. The hypothesis was that sigma-1 drugs could alter the metastatic properties of breast cancer cells via the VGSC. Evidence was found for expression of sigma-1 receptor and neonatal Nav1.5 (nNav1.5) expression in both MDA-MB-231 and MDA-MB-468 cells. Sigma-1 drugs (SKF10047 and dimethyltryptamine) did not affect cell proliferation or migration but significantly reduced adhesion to the substrate. Silencing sigma-1 receptor expression by siRNA similarly reduced the adhesion. Blocking nNav1.5 activity with a polyclonal antibody (NESOpAb) targeting an extracellular region of nNav1.5 also reduced the adhesion in both cell lines. Importantly, the results of combined treatments with NESOpAb and a sigma-1 drug or sigma-1 siRNA suggested that both treatments targeted the same mechanism. The possibility was tested, therefore, that the sigma-1 receptor and the nNav1.5 channel formed a physical, functional complex. This suggestion was supported by the results of co-immunoprecipitation experiments. Furthermore, application of sigma-1 drugs to the cells reduced the surface expression of nNav1.5 protein, which could explain how sigma-1 receptor activation could alter the metastatic behaviour of breast cancer cells. Overall, these results are consistent with the idea of a sigma-1 protein behaving like either a “chaperone” or a regulatory subunit associated with nNav1.5.

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Authors and Affiliations

  1. Institute of Ophthalmology, University College London, 11/43 Bath Street, London, EC1V 9EL, UK

    Ebru Aydar

  2. Faculty of Life Sciences, London Metropolitan University, London, N7 8DB, UK

    Dan Stratton & Christopher Palmer

  3. Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK

    Scott P. Fraser & Mustafa B. A. Djamgoz

  4. Biotechnology Research Centre (BRC), Cyprus International University, Haspolat, Lefkosa, Cyprus

    Mustafa B. A. Djamgoz

Authors
  1. Ebru Aydar
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  2. Dan Stratton
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  3. Scott P. Fraser
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  4. Mustafa B. A. Djamgoz
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  5. Christopher Palmer
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Corresponding author

Correspondence to Christopher Palmer.

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Special Issue: Ion Channels, Transporters and Cancer.

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Aydar, E., Stratton, D., Fraser, S.P. et al. Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines. Eur Biophys J 45, 671–683 (2016). https://doi.org/10.1007/s00249-016-1135-0

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  • DOI: https://doi.org/10.1007/s00249-016-1135-0

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