Voltage-gated Na+ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling

Carrie D. House, Bi Dar Wang, Kristin Ceniccola, Russell Williams, May Simaan, Jacqueline Olender, Vyomesh Patel, Daniel T. Baptista-Hon, Christina M. Annunziata, J. Silvio Gutkind, Tim G. Hales, Norman H. Lee (Lead / Corresponding author)

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    Abstract

    Functional expression of voltage-gated Na<sup>+</sup> channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.

    Original languageEnglish
    Article number11541
    Number of pages16
    JournalScientific Reports
    Volume5
    DOIs
    Publication statusPublished - 22 Jun 2015

    Fingerprint

    Colon
    Colonic Neoplasms
    Genes
    Gene Knockdown Techniques
    Gene Expression
    Small Interfering RNA
    Transcriptional Activation
    Signal Transduction
    Protein Isoforms
    Carcinogenesis
    Transcription Factors
    Pharmacology
    Cell Line
    Neoplasms

    Cite this

    House, C. D., Wang, B. D., Ceniccola, K., Williams, R., Simaan, M., Olender, J., ... Lee, N. H. (2015). Voltage-gated Na+ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling. Scientific Reports, 5, [11541]. https://doi.org/10.1038/srep11541
    House, Carrie D. ; Wang, Bi Dar ; Ceniccola, Kristin ; Williams, Russell ; Simaan, May ; Olender, Jacqueline ; Patel, Vyomesh ; Baptista-Hon, Daniel T. ; Annunziata, Christina M. ; Gutkind, J. Silvio ; Hales, Tim G. ; Lee, Norman H. / Voltage-gated Na+ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling. In: Scientific Reports. 2015 ; Vol. 5.
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    abstract = "Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.",
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    House, CD, Wang, BD, Ceniccola, K, Williams, R, Simaan, M, Olender, J, Patel, V, Baptista-Hon, DT, Annunziata, CM, Gutkind, JS, Hales, TG & Lee, NH 2015, 'Voltage-gated Na+ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling', Scientific Reports, vol. 5, 11541. https://doi.org/10.1038/srep11541

    Voltage-gated Na+ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling. / House, Carrie D.; Wang, Bi Dar; Ceniccola, Kristin; Williams, Russell; Simaan, May; Olender, Jacqueline; Patel, Vyomesh; Baptista-Hon, Daniel T.; Annunziata, Christina M.; Gutkind, J. Silvio; Hales, Tim G.; Lee, Norman H. (Lead / Corresponding author).

    In: Scientific Reports, Vol. 5, 11541, 22.06.2015.

    Research output: Contribution to journalArticle

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    AU - Hales, Tim G.

    AU - Lee, Norman H.

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