Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer

Onkal, Rustem; Djamgoz, Mustafa B.A.

doi:10.1016/j.ejphar.2009.08.040

Cited by 113 publications

(93 citation statements)

References 168 publications

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“…The efficacy of i.v.-administered encapsulated anti-RhoA siRNA in chitosancoated polyiso-hexylcyanoacrylate (PIHCA) nanoparticles in xenografted aggressive breast cancer MDA-MB-231 was demonstrated (3,4). To understand the physiopathology of breast cancer, other reports suggested that upregulation of voltage-gated Na + channels could be an accelerating factor in metastatic disease (26). The Na channel expression level appeared to be closely linked to the metastatic development in human breast cancer (19).…”

Section: Discussionmentioning

confidence: 99%

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells

Dulong

Fang

Gest

et al. 2013

International Journal of Oncology

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Abstract. Voltage-gated Na + channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels. IntroductionBreast cancer is the most commonly occurring cancer in women. Each year approximately one million of new cases occurred in the world, 25-40% of patients developing metastasis and dying from cancer (1,2). Many problems remain in its clinical management which is generally related to the malignancy types and drug resistance mechanisms as well as metastasis development. Additional investigations to understand the physiopathology of breast cancer are urgently necessary to develop new therapies based on new targets involved in cancer cell invasion and proliferation.In previous studies we have already demonstrated that the upregulation and activation of the small GTPase RhoA or RhoC contribute to cell invasion leading to breast cancer metastasis (3,4). RhoA signaling pathways are implicated in the activation of FAK, Akt/PI3K, p38MAPK and MLCK, which have been shown to be responsible for cytoskeleton actin reorganization, cell adhesion, motility, migration and invasion (5-9). In many types of cancers, RhoA appears to be overexpressed and/or constitutively activated (10,11), and considered to be a negative clinical prognosis marker (10,12,13).Recently, it has been shown that the voltage-gated Na + channels (VGSCs) could be an accelerating factor in malignant cancers (14-17). VGSCs are membrane panning proteins expressed in a wide variety of excitable and non-excitable cells, as well as in many carcinomas including breast cancer (18,19). VGSCs mainly mediate rapid and transient Na + influx into cells and are classically responsible for generation and propagation of action potential. In cancer cells, overexpression of VGSCs and/or their upregulation has been observed. In particular, the Nav1.5 channel type correlates with cancer cell invasion (20-22). Although it seems that the neonatal isoform of Nav1.5 ch...

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Section: Discussionmentioning

confidence: 99%

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells

Dulong

Fang

Gest

et al. 2013

International Journal of Oncology

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“…It is also of note that elevated NHE1 activity contributes of sodium loading of cells. Elevated sodium loading by NHE1 and other sodium loading proteins such as sodium channels and Na + /HCO3 -co-transport, may promote mitogenesis and/or oncognesis [26][27][28][29][30] and elevated tissue sodium is reported in malignant breast cancer [31] and other cancer types [32,33]. Thus elevated NHE1 activity may contribute to oncogenesis by more than one mechanism.…”

Section: Discussionmentioning

confidence: 99%

Defining the Na+/H+ exchanger NHE1 interactome in triple-negative breast cancer cells

Amith

Vincent

Wilkinson

et al. 2017

Cellular Signalling

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“…Nine isoforms of the sodium transporting a-subunit have been identified in higher vertebrates: Na V 1.1 -1.9, reviewed in (Goldin, 2001). Interestingly, it is mainly the neonatal splice variant of Na V 1.5 (nNa V 1.5) that human breast cancer cells express both in vitro and in vivo (Brackenbury et al, 2007, Fraser et al, 2005, Fraser et al, 2003, Onkal and Djamgoz, 2009, and nNa V 1.5 expression is suggested to be an integral part of the overall cancer process (Onkal and Djamgoz, 2009). Na V 1.5 is highly expressed in MDA-MB-231 breast cancer cells, less so in minimally tumourigenic MCF-7 cells, and not at all in non-tumour MCF-10A mammary epithelial cells.…”

Section: + /H + Exchanger Interactions With Other Transportersmentioning

confidence: 99%

Na+/H+ exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis?

Amith¹,

Fong²,

Baksh³

et al. 2015

Int. J. Dev. Biol.

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Ionic messengers signal several critical events in carcinogenesis, including metastasis, the leading cause of patient mortality. The aberrant metabolic, proliferative and anti-apoptotic nature of neoplastic cells can be traced to the abnormal expression of their ion transporters and related signalling networks. In this manuscript, we discuss Na + /H + flux, as mediated by the sodium-hydrogen exchanger isoform 1 (NHE1), a major ion transporter involved in tumourigenesis. Allosteric activation of NHE1 by external stimuli is controlled by phosphorylation of key amino acids on its cytosolic Cterminal tail, which also acts as a signal scaffold for its regulation by intracellular protein and lipid binding partners. In breast cancer cells, pH homeostasis and proton dynamics are disrupted early in transformation. This constitutively activates NHE1, causing a reversal of the plasma membrane pH gradient, resulting in a more alkaline intracellular pH and a more acidic extracellular pH. NHE1-mediated cellular alkalinization potentiates cytoskeletal remodelling, mobilizing cells for directed migration. Concomitant redistribution of NHE1 to invadopodia, where increased proton extrusion promotes proteolytic digestion of the extracellular matrix, primes cells for invasion into the bloodstream. NHE1 hyperactivity therefore heralds an important stage in cancer cell development, critically facilitating the acquisition of the invasive phenotype necessary for metastasis to occur. The potential for targeting NHE1 in the development of novel chemotherapeutic applications is explored.

show abstract

Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer

Cited by 113 publications

References 168 publications

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells

Defining the Na+/H+ exchanger NHE1 interactome in triple-negative breast cancer cells

Na+/H+ exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis?

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