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Title: Functional involvement of voltage-gated Na+ channels in regulation of membrane potential in MDA-MB-231 human breast cancer cells
Author: Yang, Ming
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2015
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Voltage-gated Na+ channels (VGSCs) initiate and propagate action potentials in neurones. Functional VGSCs have been found in an increasing number of cancer cells and patient biopsies from different tissues. Blocking VGSCs using pharmacological agents or suppressing VGSC expression using RNA interference reduces cell metastatic behaviour, such as migration and invasion in vitro and metastasis in vivo in rodent models. In breast cancer, a high mRNA level of Nav1.5, a VGSC isoform, correlates with metastasis and poor prognosis. However, the detailed mechanism(s) underlying VGSC-dependent metastatic cell behaviours is not fully understood. Depolarised membrane potential (Vm) induces mitotic activity in neurones and causes tumourigenesis in Xenopus laevis. Given that VGSCs depolarise the Vm upon action potential firing in neurones, using MDA-MB-231 human breast cancer cells where VGSCs are endogenously expressed, the present study hypothesised that VGSCs increase cell metastatic behaviours by depolarising the Vm. This study found that VGSCs depolarise the Vm of MDA-MB-231 cells by ~4 mV. Hyperpolarising the Vm by blocking VGSCs with tetrodotoxin (TTX) or activating large conductance Ca2+-activated K+ channels using NS-1619 slowed cell migration to a similar extent. Rac1 is a small GTPase that potentiates cell migration via facilitating actin filament assembly. Both TTX and NS-1619 reduced the active Rac1 level at the leading edge of cells, suggesting that Vm controls Rac1 activity/distribution and henceforth cell motility in MDA-MB-231 cells. However, MDA-MB-231 cell invasion was inhibited by TTX but not NS-1619, suggesting that Na+, rather than Vm, may be the factor that underlies VGSC-dependent cell invasion. Finally, this study recorded Na+ current carried by VGSCs in tumour cells in tissue slices from mice, suggesting that VGSCs are functional in vivo. In summary, the present study provides novel evidence elucidating mechanisms underlying VGSC-dependent metastatic cell behaviours. Future experiments should explore VGSC/Vm as potential therapeutic targets in cancer treatment.
Supervisor: Yang, Ming ; Brackenbury, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available