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

Aydar, Ebru and Stratton, Dan and Fraser, Scott and Djamgoz, Mustafa and Palmer, Christopher P. (2016) Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines. European Biophysics Journal. ISSN 0175-7571

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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.

Item Type: Article
Uncontrolled Keywords: Sigma-1 receptor, Sodium channel, Metastasis
Subjects: 500 Natural Sciences and Mathemetics > 570 Life sciences; biology
600 Technology > 610 Medicine & health
Department: School of Human Sciences
Depositing User: Chris Palmer
Date Deposited: 13 May 2016 08:14
Last Modified: 20 May 2016 10:36
URI: http://repository.londonmet.ac.uk/id/eprint/997

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