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#36183245   2022/10/02 To Up

Sodium channels and the ionic microenvironment of breast tumours.

Cancers of epithelial origin such as breast, prostate, cervical, gastric, colon and lung cancer account for a large proportion of deaths worldwide. Better treatment of metastasis, the main cause of cancer deaths, is therefore urgently required. Several of these tumours have been shown to have an abnormally high concentration of Na ([Na ]) and emerging evidence points to this accumulation being due to elevated intracellular [Na ]. This poses intriguing questions about the cellular mechanisms underlying Na dysregulation in cancer, and its pathophysiological significance. Elevated intracellular [Na ] may be due to alterations in activity of the Na /K ATPase, and/or increased influx via Na channels and Na -linked transporters. Maintenance of the electrochemical Na gradient across the plasma membrane is vital to power many cellular processes that are highly active in cancer cells, including glucose and glutamine import. Na channels are also upregulated in cancer cells, which in turn promote tumour growth and metastasis. For example, ENaC and ASICs are overexpressed in cancers increasing invasion and proliferation. In addition, voltage-gated Na channels are also upregulated in a range of tumour types, where they promote metastatic cell behaviours via various mechanisms, including membrane potential depolarisation and altered pH regulation. Together, recent findings relating to elevated Na in the tumour microenvironment and how this may be regulated by several classes of Na channels, provide a link between altered Na handling and poor clinical outcome. There are new opportunities to leverage this altered Na microenvironment for therapeutic benefit, as exemplified by several ongoing clinical trials. Abstract figure legend Mechanisms of Na channel and transporter-dependent proliferation, migration, and invasion. Na enters through VGSC, ENaC and ASIC channels and through the SGLT2 cotransporter and the NHE1 exchanger. These mechanisms may be responsible for elevating intracellular [Na ]. Na is removed from the cell via the Na /K ATPase. VGSCs depolarise the cell membrane potential (V ), which leads to increased migration. VGSCs also regulate transcription of genes involved in proliferation, migration and invasion. VGSCs increase the activity of NHE1, further elevating intracellular [Na ] and extracellular [H ]. This acidifies the extracellular environment and aids cellular invasion through extracellular matrix. The low extracellular pH will then affect the Na channels, increasing the inward Na current through these in a positive feedback mechanism which increases intracellular [Na ] and extracellular [H ]. This article is protected by copyright. All rights reserved.
Theresa K Leslie, William J Brackenbury

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