title: Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling.
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.
authors.affiliation: 1] Department of Pharmacology and Physiology, The George Washington University, Washington, DC [2] Women's Malignancies Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Carrie D
authors.initials: CD
authors.lastname: House
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors.forename: Bi-Dar
authors.initials: BD
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ceniccola
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors.forename: Russell
authors.initials: R
authors.lastname: Williams
authors.affiliation: The National Institute of Dental and Craniofacial Research, Bethesda, MD.
authors.forename: May
authors.initials: M
authors.lastname: Simaan
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Olender
authors.affiliation: The National Institute of Dental and Craniofacial Research, Bethesda, MD.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: The Institute of Academic Anaesthesia, Division of Neuroscience, Ninewells Hospital, University of Dundee, Dundee, DD1 9SY, UK.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Baptista-Hon
authors.affiliation: Women's Malignancies Branch, National Cancer Institute, Bethesda, MD.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.affiliation: The National Institute of Dental and Craniofacial Research, Bethesda, MD.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: The Institute of Academic Anaesthesia, Division of Neuroscience, Ninewells Hospital, University of Dundee, Dundee, DD1 9SY, UK.
authors.forename: Tim G
authors.initials: TG
authors.lastname: Hales
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D014701:Veratridine / Q000494:pharmacology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D034741:RNA, Small Interfering; C568320:SCN5A protein, human; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D014701:Veratridine; D048049:Extracellular Signal-Regulated MAP Kinases