Format

Send to

Choose Destination
Sci Rep. 2015 Jun 22;5:11541. doi: 10.1038/srep11541.

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling.

Author information

1
1] Department of Pharmacology and Physiology, The George Washington University, Washington, DC [2] Women's Malignancies Branch, National Cancer Institute, Bethesda, MD.
2
Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
3
The National Institute of Dental and Craniofacial Research, Bethesda, MD.
4
The Institute of Academic Anaesthesia, Division of Neuroscience, Ninewells Hospital, University of Dundee, Dundee, DD1 9SY, UK.
5
Women's Malignancies Branch, National Cancer Institute, Bethesda, MD.

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.

PMID:
26096612
PMCID:
PMC4476109
DOI:
10.1038/srep11541
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center