Abstract 5292: Role of voltage-gated Na+ channels in the metastatic potential of colon cancer cells

Abstract

Abstract Ion channels are major signaling proteins spanning the plasma membrane where they enable the diffusion of specific ions into and out of a variety of cells. Voltage-gated Na+ channels (VGSCs) are responsible for the depolarization phase of neuronal action potentials and their activity is required for neurite extension and neurotransmitter release. Aberrant expression of VGSCs has recently been implicated in cancer. Overexpression of VGSCs appears to be associated with increased motility and invasive potential in vitro, whereas treatment with pharmacological agents that block Na+ currents, significantly reduce invasion. We have recently identified functional VGSCs in SW480, SW620, and HT29 colon cancer cells and examined their role in invasion. Electrophysiological techniques were employed to confirm functional expression of the SCN5A isoform in colon cancer cells. The more invasive SW620 cell line has a higher current density and increased protein expression compared to the less invasive SW480 and HT29 cell lines. Furthermore, we used RNA interference and VGSC blockers (tetrodotoxin and lidocaine) to inhibit channel expression and activity, respectively, and demonstrated a loss of invasive potential. Conversely, treatment with veratridine, a neurotoxin that prevents complete inactivation of VGSCs, increased Na+ influx and led to higher invasive potential. In addition to colon cancer cell lines, the expression of Nav1.5, the protein encoded by SCN5A, was examined in colon cancer patient samples by immunohistochemistry. Expression of this channel was restricted to the lumen of colon cancer specimens when compared to their normal matched controls. The contribution of this channel to metastatic behavior has not been previously demonstrated in colon cancer. To facilitate a further understanding of the mechanism by which this channel induces invasive potential, we have analyzed the involvement of SCN5A in activation of the MAPK pathway, which is deregulated in many cancers. Coincidentally, this pathway is also activated after depolarization in neurons during neurogenesis. Lastly, we show that SCN5A participates in the regulation of a colon cancer transcriptional network important for invasion. Taken together, our data suggest that VGSCs contribute to the metastatic potential of colon cancer cells through activation of the MAPK pathway and transcriptional regulation of genes important for the invasion process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5292.