Document Type
Journal Article
Publication Date
2015
Journal
Scientific Reports
Volume
5
Inclusive Pages
11541
DOI
10.1038/srep11541
Keywords
Colonic Neoplasms--genetics; MAP Kinase Signaling System--genetics; NAV1.5 Voltage-Gated Sodium Channel--genetics; Neoplasm Invasiveness--genetics; Transcription, Genetic--genetics
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
APA Citation
House, C.D., Wang, B., Ceniccola, K., Williams, R., Simaan, M. et al. (2015). Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling. Scientific Reports, 5: 11541.
Open Access
1
Comments
Reproduced with permission of Nature Publishing Group. Scientific Reports.