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

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.

• Authors: Ebru Aydar, Dan Stratton, Scott P Fraser, Mustafa B A Djamgoz, Christopher Palmer
• Journal: European biophysics journal : EBJ (Eur Biophys J) Vol. 45 Issue 7 Pg. 671-683 (Oct 2016) ISSN: 1432-1017 [Electronic] Germany
• PMID: 27160185 (Publication Type: Journal Article)

Chemical References

• NAV1.5 Voltage-Gated Sodium Channel
• Receptors, sigma
• SCN5A protein, human

Topics

• Breast Neoplasms (pathology)
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Gene Silencing
• Humans
• Infant, Newborn
• NAV1.5 Voltage-Gated Sodium Channel (metabolism)
• Neoplasm Metastasis
• Receptors, sigma (deficiency, genetics, metabolism)
• Sigma-1 Receptor