Abstract
Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na+ channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer.
Highlights
It is well established that de novo expression of voltage-gated ion channels (VGICs) occurs in cancers in vitro and in vivo and plays a significant role in disease initiation and progression [1,2,3,4,5,6]
Produced the following significant effects: (i) the nNav1.5 mRNA level was increased by 211 + 49%; (ii) the proportion of cells expressing functional VGSCs was increased by more than three-fold; and (iii) the lateral motility of the cells was increased by 23 + 5%. These results suggest that steady-state VGSC expression is upregulated transcriptionally in the absence of ERa expression/activity, in general agreement with ERa-negative (VGSC-expressing) cases of breast cancer (BCa) being more aggressive [58]
The SCN9A promoter in human prostate cancer (PCa) PC-3 cells was shown to be activated by nerve growth factor (NGF) [94]. While it appears that NGF can affect both VGSC expression and cancer cell motility, further work is required to clarify the connection between the two effects and the nature of the associated receptor and downstream signalling mechanisms
Summary
It is well established that de novo expression of voltage-gated ion channels (VGICs) occurs in cancers in vitro and in vivo and plays a significant role in disease initiation and progression [1,2,3,4,5,6]. In the case of breast cancer (BCa), the oncofetal/neonatal isoform of Nav1.5 (nNav1.5) would allow greater Naþ entry into the cell, compared with the adult splice variant [26] This could have implications for Naþ –Hþ exchange and intra/extracellular pH regulation [27]; enzyme activity, e.g. Naþ/Kþ-ATPase and protein kinase A [27,28]; and Ca2þ homeostasis, e.g. Naþ – Ca2þ exchange [29]. The mechanisms underlying the involvement of VGSCs in such cell behaviours are not well characterized, several suggestions have been made These include (i) interaction with cytoskeletal elements (and/or b-subunits) and (ii) modulation of ion fluxes/exchangers, gene expression and enzyme activity [8,18,32,39,49,50]. For completeness, we cover some essential non-cancer examples
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