Abstract
ABSTRACTVoltage-gated sodium channel (Nav) expression in non-excitable cells has raised questions regarding their non-canonical roles. Interestingly, a growing body of evidence also points towards the prevalence of aberrant Nav expression in malignant tumors, potentially opening a new therapeutic window. In this study, the transcriptional consequences of channel inhibition were investigated in non-small cell lung carcinoma H460 and neuroblastoma SH-SYSY cell lines, that both express Nav1.7. Channel activity was blocked by the application of both selective, ProTx-II, and non-selective, tetrodotoxin, inhibitors. Global gene expression profiling did not point to any statistically significant inhibition-associated perturbation of the transcriptome. A small subset of genes that showed relatively consistent changes across multiple treatments were further assayed in the context of a multiplex bead expression array which failed to recapitulate the changes seen in the global array. We conclude that there is no robust transcriptional signature associated with the inhibition of two sodium channel expressing cancer cell lines and consequently sodium channel inhibition will not lend itself to therapeutic approaches such as transcription-based drug repurposing.
Highlights
Voltage-gated sodium (Nav) channels were originally characterized as prominent players in signal conduction in excitable cells, such as neurons and myocytes, principally through the regulation of cellular ion balance [1,2]
The top 1000 genes in the H460 and SH-SY5Y or SHSY rank profiles are overwhelmingly up-regulated consisting of (977 upregulated and 23 down-regulated) for H460 and (950 up-regulated and 50 down-regulated) for SHSY. These profiles served as queries in the SPIED search. It is perhaps worth pointing out here that the level of gene expression unique to a given cell type will tend to be elevated relative to a background consisting of a variety of tissue types
The top SPIED hits show a high correlation with appropriate cell types, validating the cell lineages, with the H460 query resulting in exclusively H460 profiles, Figure 1(a)
Summary
Voltage-gated sodium (Nav) channels were originally characterized as prominent players in signal conduction in excitable cells, such as neurons and myocytes, principally through the regulation of cellular ion balance [1,2]. The expression of Nav channels in these cells is dynamic, and may alter depending on the developmental, physiological, and pathological state [12,13]. This dynamic expression profile has been linked to distinct biological states of the cell serving to implement diverse biological functions, e.g. motility, endosomal acidification, and phagocytosis [14,15]
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