Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation.
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.
Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, , South Kensington Campus, London SW7 2AZ, UK.
Scott P
SP
Fraser
Iley
I
Ozerlat-Gunduz
William J
WJ
Brackenbury
Elizabeth M
EM
Fitzgerald
Thomas M
TM
Campbell
R Charles
RC
Coombes
Mustafa B A
MB
Djamgoz
D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006728:Hormones / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; D061566:Voltage-Gated Sodium Channels
activity-dependent regulation; growth factor; hormone; metastasis; voltage-gated sodium channel