Contribution of functional voltage‐gated Na⁺ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. lateral motility

Abstract

Previous work suggested that functional voltage-gated Na(+) channels (VGSCs) are expressed specifically in strongly metastatic cells of rat and human prostate cancer (PCa), thereby raising the possibility that VGSC activity could be involved in cellular behavior(s) related to the metastatic cascade. In the present study, the possible role of VGSCs in the lateral motility of rat PCa cells was investigated in vitro by testing the effect of modulators that either block or enhance VGSC activity. Two rat PCa cell lines of markedly different metastatic ability were used in a comparative approach: the strongly metastatic MAT-LyLu and the weakly metastatic AT-2 cell line, only the former being known to express functional VGSCs. Using both electrophysiological recording and a motility assay, the effects of two VGSC blockers (tetrodotoxin and phenytoin) and four potential openers (veratridine, aconitine, ATX II, and brevetoxin) were monitored on (a) Na(+) channel activity and (b) cell motility over 48 h. Tetrodotoxin (at 1 microM) and phenytoin (at 50 microM) both decreased the motility index of the MAT-LyLu cell line by 47 and 11%, respectively. Veratridine (at 20 microM) and brevetoxin (at 10 nM) had no effect on the motility of either cell line, whilst aconitine (at 100 microM) and ATX II (at 25 pM) significantly increased the motility of the MAT-LyLu cell line by 15 and 9%, respectively. Importantly, at the concentrations used, none of these drugs had effects on the proliferation or viability of either cell line. The results, taken together, would suggest strongly that functional VGSC expression enhances cellular motility of PCa cells. The relevance of these findings to the metastatic process in PCa is discussed.

Brn-3a neuronal transcription factor functional expression in human prostate cancer

“…29,[31][32][33] In this study, we observed Brn3a[s]-specific transcriptional regulation of SCN9A/Nav1.7 in PC-3 cells with both stable and transient overexpression of this transcription factor. This is the first example of gene regulation by the short isoform of a Brn-3 protein only.…”

“…The Nav1.7 VGSC has been shown to potentiate cellular processes integral to CaP metastasis in vitro, especially invasion 27,[31][32][33] and VGSCs have been found to increase the invasiveness of lymphocytes and breast cancer cells. 49,51 Brn-3 proteins have also recently been found to have a role in cellular invasion, with overexpression of Brn-3b significantly potentiating neuroblastoma cell invasion through Matrigel.…”

Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

“…A similar mechanism of action of sodium channel blockade also may be relevant in tumor cell biology. In neoplastic cells that express intracellular sodium channels, particularly NaV1.6-positive melanomas, functional block of sodium channels might prevent metastasis through both a direct interaction with the tumor cell as well as effects on macrophages and endothelial cells (9,34,35). Additional studies are required to assess the therapeutic potential of sodium channel blockers in these disease states.…”

“…Unlike NaV1.5, NaV1.6 is also expressed in unprimed human macrophages and in unprimed and primed mouse macrophages and microglia (7,8). Many invasive neoplastic cell lines also express voltage-gated sodium channels, which may regulate their ability to metastasize (9).…”

Repression of SHP-1 expression by p53 leads to trkA tyrosine phosphorylation and suppression of breast cancer cell proliferation

“…MTT assay A total of 2 Â 10 3 cells per well were plated in 96-well plates with 200 ml media per well as control (Fraser et al, 2003). Cells were washed with serum-free media, and incubated with serum-free media with or without 100 ng/ml of NGF and dimethyl sulfoxide (DMSO) or 1 mM AG1478, AG825 or AG1295 for 48 h at 32 or 37 1C.…”