title: 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.affiliation: Institute of Ophthalmology, University College London, 11/43 Bath Street, London, EC1V 9EL, UK.
authors.forename: Ebru
authors.initials: E
authors.lastname: Aydar
authors.affiliation: Faculty of Life Sciences, London Metropolitan University, London, N7 8DB, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Stratton
authors.affiliation: Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Fraser
authors.affiliation: Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, Sir Alexander Fleming Building, London, SW7 2AZ, UK.|Biotechnology Research Centre (BRC), Cyprus International University, Haspolat, Lefkosa, Cyprus.
authors.forename: Mustafa B A
authors.initials: MB
authors.lastname: Djamgoz
authors.affiliation: Faculty of Life Sciences, London Metropolitan University, London, N7 8DB, UK. chris.palmer@londonmet.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Palmer
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D020868:Gene Silencing; D006801:Humans; D007231:Infant, Newborn; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009362:Neoplasm Metastasis; D017480:Receptors, sigma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C568320:SCN5A protein, human
keywords: Metastasis; Sigma-1 receptor; Sodium channel