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

Stratton, Daniel; Aydar, Ebru; Stratton, Dan; Fraser, Scott P.; Djamgoz, Mustafa B.A.; Palmer, Christopher


Ebru Aydar

Scott P. Fraser

Mustafa B.A. Djamgoz

Christopher Palmer


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.

Journal Article Type Article
Publication Date Oct 1, 2016
Print ISSN 0175-7571
Electronic ISSN 1432-1017
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 45
Issue 7
Pages 671-683
APA6 Citation Aydar, E., Stratton, D., Fraser, S. P., Djamgoz, M. B., & Palmer, C. (2016). Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines. European Biophysics Journal, 45(7), 671-683. doi:10.1007/s00249-016-1135-0
Keywords Sigma-1 receptor; Sodium channel; Metastasis
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