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Article Open Access

Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells

  • Authors:
    • Fatima H. Mohammed
    • Maitham A. Khajah
    • Ming Yang
    • William J. Brackenbury
    • Yunus A. Luqmani
  • View Affiliations / Copyright

    Affiliations: Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait, Department of Biology, University of York, Heslington, York, YO10 5DD, UK
    Copyright: © Mohammed et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Pages: 73-83
    |
    Published online on: November 9, 2015
       https://doi.org/10.3892/ijo.2015.3239
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Abstract

Voltage-gated Na+ channels (VGSCs) are membrane proteins which are normally expressed in excitable cells but have also been detected in cancer cells, where they are thought to be involved in malignancy progression. In this study we examined the ion current and expression profile of VGSC (Nav1.5) in estrogen receptor (ER)-positive (MCF-7) and silenced (pII) breast cancer cells and its possible influence on their proliferation, motility and invasion. VGSC currents were analysed by whole cell patch clamp recording. Nav1.5 expression and localization, in response to EGF stimulation, was examined by western blotting and immunofluorescence respectively. Cell invasion (under-agarose and Matrigel assays), motility (wound healing assay) and proliferation (MTT assay) were assessed in pII cells in response to VGSC blockers, phenytoin (PHT) and tetrodotoxin (TTX), or by siRNA knockdown of Nav1.5. The effect of PHT and TTX on modulating EGF-induced phosphorylation of Akt and ERK1/2 was determined by western blotting. Total matrix metalloproteinase (MMP) was determined using a fluorometric-based activity assay. The level of various human proteases was detected by using proteome profiler array kit. VGSC currents were detected in pII cells, but were absent in MCF-7. Nav1.5 showed cytoplasmic and perinuclear expression in both MCF-7 and pII cells, with enhanced expression upon EGF stimulation. Treatment of pII cells with PHT, TTX or siRNA significantly reduced invasion towards serum components and EGF, in part through reduction of P-ERK1/2 and proteases such as cathepsin E, kallikrein-10 and MMP-7, as well as total MMP activity. At high concentrations, PHT inhibited motility while TTX reduced cell proliferation. Pharmacological or genetic blockade of Nav1.5 may serve as a potential anti-metastatic therapy for breast cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Mohammed FH, Khajah MA, Yang M, Brackenbury WJ and Luqmani YA: Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells. Int J Oncol 48: 73-83, 2016.
APA
Mohammed, F.H., Khajah, M.A., Yang, M., Brackenbury, W.J., & Luqmani, Y.A. (2016). Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells. International Journal of Oncology, 48, 73-83. https://doi.org/10.3892/ijo.2015.3239
MLA
Mohammed, F. H., Khajah, M. A., Yang, M., Brackenbury, W. J., Luqmani, Y. A."Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells". International Journal of Oncology 48.1 (2016): 73-83.
Chicago
Mohammed, F. H., Khajah, M. A., Yang, M., Brackenbury, W. J., Luqmani, Y. A."Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells". International Journal of Oncology 48, no. 1 (2016): 73-83. https://doi.org/10.3892/ijo.2015.3239
Copy and paste a formatted citation
x
Spandidos Publications style
Mohammed FH, Khajah MA, Yang M, Brackenbury WJ and Luqmani YA: Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells. Int J Oncol 48: 73-83, 2016.
APA
Mohammed, F.H., Khajah, M.A., Yang, M., Brackenbury, W.J., & Luqmani, Y.A. (2016). Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells. International Journal of Oncology, 48, 73-83. https://doi.org/10.3892/ijo.2015.3239
MLA
Mohammed, F. H., Khajah, M. A., Yang, M., Brackenbury, W. J., Luqmani, Y. A."Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells". International Journal of Oncology 48.1 (2016): 73-83.
Chicago
Mohammed, F. H., Khajah, M. A., Yang, M., Brackenbury, W. J., Luqmani, Y. A."Blockade of voltage-gated sodium channels inhibits invasion of endocrine-resistant breast cancer cells". International Journal of Oncology 48, no. 1 (2016): 73-83. https://doi.org/10.3892/ijo.2015.3239
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