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• W2000368946 abstract "An interesting new field in cancer research is the role of voltage-gated Na + channels (VGSCs) in cancer cell invasion. Expression of these ion channels is normally restricted to excitable cells, such as neurons, however functional expression has been demonstrated in multiple cancer cell types where channel activity leads to changes in invasion potential in vitro. We have recently demonstrated functional expression of Na v 1.5, a protein encoded by SCN5A, in a variety of colon cancer cell lines. We showed that pharmacological inhibition of channel activity leads to a decrease in invasion potential, whereas pharmacological activation of the channel leads to an increase in invasion potential. Moreover, upon examination of patient samples we found that protein expression is restricted to malignant tissue. What has remained largely uncharacterized is the mechanism by which these channels promote oncogenic behavior. We have recently established that VGSC isoform SCN5A participates in an invasion gene network for colon cancer, regulating expression of several genes important for invasion. Our current study focuses on determining what non-genomic signaling pathway(s) are activated in response to VGSC activity that might lead gene expression changes. The MAPK pathway is deregulated in many cancers and VGSC activation in neurons leads to MAPK activation during neurogenesis. Coincidentally, many genes regulated by SCN5A have binding sites for transcription factors phosphorylated by ERK1/2. We hypothesized that VGSC activation promotes MAPK activation in colon cancer cells to provide an oncogenic advantage. Using pharmacological inhibition of MAPK, we demonstrate the requirement of this molecule for colon cancer invasion in vitro. Furthermore, we show through Western blot analysis of phosphorylated ERK1/2, that MAPK activity is diminished when colon cancer cells are treated with VGSC inhibitor, lidocaine, and persistently enhanced for 24-48 hours in the presence of the VGSC activator, veratridine. This persistent activation and the increase in invasion potential are partially lost when veratridine is used in the presence of a PKA inhibitor. Similarly, veratridine treatment in the presence of a siRNA directed against Rap1 leads to a decrease in both invasion potential and MAPK activity compared to veratridine alone. Lastly, we demonstrate increased Src activity after treatment with veratridine. Taken together, our data suggest that VGSC activation leads to an increase in MAPK activity through activation of PKA, Rap1 and Src in colon cancer cells. We further show that Rap1 activation is biphasic with early persistent signaling likely through PKA and delayed persistent signaling through Src. The proposed signaling pathway illustrates for the first time a potential mechanism by which VGSC activity promotes oncogenesis in colon cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1418. doi:10.1158/1538-7445.AM2011-1418" @default.
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• W2000368946 date "2011-04-15" @default.
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• W2000368946 title "Abstract 1418: Voltage-gated Na+channel activation leads to increased invasion potential through persistent MAPK signaling involving PKA, Src, and Rap1" @default.
• W2000368946 doi "https://doi.org/10.1158/1538-7445.am2011-1418" @default.
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