NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

Brisson, Lucie; Gillet, Ludovic; Calaghan, Sarah; Besson, Pierre; Guennec, Jean‐Yves Le; Roger, Sébastien; Goré, J.

doi:10.1038/onc.2010.574

Cited by 176 publications

(212 citation statements)

References 26 publications

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“…Interestingly, we have shown in this study that NHE7-overexpression facilitates tumor invasion, cell-overlay and tumor formation in vivo. NHE1 is known to facilitate tumor invasion by acidifying the local pH and thereby activating pH-sensitive enzymes that degrade the extracellular matrix (9, [40][41][42][43][44][45]. In agreement, we also showed that overexpression of NHE1 in MDA-MB-231 cells enhances cell invasion (N1 in Fig.…”

Section: Discussionsupporting

confidence: 77%

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Onishi

Lin²,

Numata³

et al. 2011

Oncol Rep

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Abstract. Na+ /H + exchangers (NHEs) are a group of secondary active antiporters that regulate cellular pH, cell volume and ion homeostasis. In humans, nine isoforms (NHE1-NHE9) were identified and characterized as functional NHEs. While a growing body of evidence indicates that NHE1 generates an acidic tumor environment and thereby contributes to tumor invasion, little is known about the role of other NHE isoforms in tumor progression. NHE7 is a unique member of the NHE gene family that dynamically shuttles between the trans-Golgi network, endosomes and the plasma membrane, and regulates the luminal pH of these organelles. Here we show that NHE7-overexpression in breast cancer MDA-MB-231 cells enhances cell overlay, cell-cell adhesion, invasion, anchorage-independent tumor growth and tumor formation in vivo. In contrast, NHE1-overexpression enhances tumor invasion, but it has little effect on cell adhesion or anchorageindependent tumor growth. Pathological examinations of the tumor samples derived from NHE7-overexpressing cells showed a similar appearance to aggressive tumors. Together, these results suggest that NHE7 enhances tumor progression. This is the first report to show the involvement of an organellar NHE in oncogenic processes.

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Section: Discussionsupporting

confidence: 77%

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Onishi

Lin²,

Numata³

et al. 2011

Oncol Rep

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“…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)(21)(22). Although it seems that the neonatal isoform of Nav1.5 channel may be a potential target for cancer therapy, so far the mechanisms regulating its expression and its functional activity in cancer cells have not been clarified.…”

Section: Introductionmentioning

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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“…The acquisition of functional Na v , thus appears to accelerate development of cancer metastases in a variety of carcinomas. However, details of the downstream effects of Na v (Brisson et al, 2011;Gillet et al, 2009) and the cellular mechanism(s) that regulate their expression and activity in metastatic cells remain unclear (Ding et al, 2008;Uysal-Onganer and Djamgoz, 2007).…”

Section: Introductionmentioning

confidence: 99%

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

Campbell¹,

Main²,

FitzGerald³

2013

Journal of Cell Science

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SummaryVarious ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, invasion and metastasis. Expression of functional voltage-gated Na + channels (Na v ) is implicated in the metastatic potential of breast, prostate, lung and colon cancer cells. However, the cellular mechanisms that regulate Na v expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, we examine the role of epidermal growth factor receptor (EGFR) signalling and Na v in non-small cell lung carcinoma (NSCLC) cell lines. We show unequivocally, that functional expression of the a subunit Na v 1.7 promotes invasion in H460 NSCLC cells. Inhibition of Na v 1.7 activity (using tetrodotoxin) or expression (by using small interfering RNA), reduces H460 cell invasion by up to 50%. Crucially, non-invasive wild type A549 cells lack functional Na v , whereas exogenous overexpression of the Na v 1.7 a subunit is sufficient to promote TTX-sensitive invasion of these cells. EGF/EGFR signalling enhances proliferation, migration and invasion of H460 cells but we find that, specifically, EGFR-mediated upregulation of Na v 1.7 is necessary for invasive behaviour in these cells. Examination of Na v 1.7 expression at mRNA, protein and functional levels further reveals that EGF/ EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of channel expression to promote cellular invasion. Immunohistochemistry of patient biopsies confirms the clinical relevance of Na v 1.7 expression in NSCLC. Thus, Na v 1.7 has significant potential as a new target for therapeutic intervention and/or as a diagnostic or prognostic marker in NSCLC.

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NaV1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae

Cited by 176 publications

References 26 publications

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

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

Functional expression of the voltage-gated sodium channel, Nav1.7, underlies epidermal growth factor-mediated invasion in human [R1.S1] non-small cell lung cancer cells

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