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

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.

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

• Journal Article Type: Article
• Acceptance Date: Apr 20, 2016
• Online Publication Date: May 9, 2016
• Publication Date: Oct 1, 2016
• Deposit Date: Jul 4, 2018
• Publicly Available Date: Oct 27, 2022
• Print ISSN: 0175-7571
• Electronic ISSN: 1432-1017
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 45
• Issue: 7
• Pages: 671-683
• DOI: https://doi.org/10.1007/s00249-016-1135-0
• Keywords: Sigma-1 receptor; Sodium channel; Metastasis
• Public URL: https://hull-repository.worktribe.com/output/910430
• Publisher URL: https://link.springer.com/article/10.1007%2Fs00249-016-1135-0
• Related Public URLs: http://repository.londonmet.ac.uk/997/