Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation

Scott P Fraser, Iley Ozerlat-Gunduz, William J Brackenbury, Elizabeth M Fitzgerald, Thomas M Campbell, R Charles Coombes, Mustafa B A Djamgoz

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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.
Original languageEnglish
Article number20130105
Number of pages12
JournalPhilosophical Transactions Of The Royal Society Of London Series B - Biological Sciences
Issue number1638
Early online date3 Feb 2014
Publication statusPublished - 19 Mar 2014

Bibliographical note

©2014 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License, which permits unrestricted use, provided the original authors and source are credited.

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