Mustafa B.A. Djamgoz
Voltage-gated Na+ channel hyperactivity and control of metastatic cell behaviours in breast and prostate cancer
In an electro-physiological approach to understanding the pathophysiology of metastatic disease, we have found that strongly metastatic cells express voltage-gated Na+ channels (VGSCs) in neonatal splice forms. Most work has been done on breast cancer (BCa) and prostate cancer (PCa) where VGSC activity potentiates a range of metastatic cell behaviours, including "motility" (Fraser et al.,2003, 2005; Brackenbury et al.,2007). This presentation will highlight a number of aspects of cancer cell motility in relation to VGSC control, as follows:
1.Types of motility. Cellular motility has been measured and quantified in a number of ways: a) 'wound-heal' assays [cf. early, lateral local motile activity]; (b) 'transverse migration' [cf. intra/extravasation]; and (c) 'galvanotaxis' [cf. (b) taking into account also local field or trans-cellular voltage gradients]. All three types of cellular motility were suppressed significantly by suppressing VGSC activity using the highly specific blocker, tetrodotoxin (TTX). In the case of MDA-MB-231 BCa cells, even ~30% reduction in VGSC (neonatal Nav1.5) activity by siRNA completely removed the VGSC-dependent enhancement of motility.
2.Mechanisms upstream of VGSC expression. Our data are consistent with VGSC upregulation occurring when BCa and PCa becomes hormone-independent and switches to dependence on growth factors. Two major growth factors were found to be involved in PCa: Nerve growth factor and epidermal growth factor (EGF). Although both potentiated motile activity, it was only EGF that signalled through VGSCs. Interestingly, in media containing a high level of insulin, VGSC activity suppressed motility, raising the possibility of cellular motility being under servo-like control.
3.Mechanisms downstream of functional VGSC expression / activity. We know much less about these. On the whole, there are two sets of possibilities: a) protein-protein interactions and (b) enzyme activity stimulated by VGSC-mediated Na+ influx and/or subsequent changes in intracellular Ca2+ or pH. As an example of the latter, evidence will be presented for VGSC/Na+-dependent PKA activity.

Brackenbury WJ et al. (2007). The neonatal splice variant of Nav1.5 potentiates in vitro invasive behaviour of MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat. 101 : 149-160.
Fraser SP et al. (2005). Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin Cancer Res. 11 : 5381-5389.
Fraser SP et al. (2003). Contribution of functional voltage-gated Na+ channel expression to cell behaviours involved in the metastatic cascade in rat prostate cancer. I Lateral motility. J Cell Physiol 195: 479-487.