How do voltage-gated sodium channels enhance migration and invasiveness in cancer cells?

Besson, Pierre; Driffort, Virginie; Bon, Émeline; Gradek, Frédéric; Chevalier, Stéphan; Roger, Sébastien

doi:10.1016/j.bbamem.2015.04.013

Cited by 89 publications

(86 citation statements)

References 93 publications

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“…There is growing evidence that cancer cell hallmarks are strongly regulated by ion channels including K + [5], [6], [7], Ca 2+ [8], [9], [10], and Na + channels [11], [12]. In particular, several channels including transient receptor potential (TRP) channels are implicated in molecular mechanisms of the metastatic cascade [4].…”

Section: Introductionmentioning

confidence: 99%

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to better understand the molecular mechanisms that regulate PDAC cell aggressiveness. The transient receptor potential melastatin 7 (TRPM7) is a nonselective cationic channel that mainly conducts Ca2+ and Mg2+. TRPM7 is overexpressed in numerous malignancies including PDAC. In the present study, we used the PANC-1 and MIA PaCa-2 cell lines to specifically assess the role of TRPM7 in cell invasion and matrix metalloproteinase secretion. We show that TRPM7 regulates Mg2+ homeostasis and constitutive cation entry in both PDAC cell lines. Moreover, cell invasion is strongly reduced by TRPM7 silencing without affecting the cell viability. Conditioned media were further studied, by gel zymography, to detect matrix metalloproteinase (MMP) secretion in PDAC cells. Our results show that MMP-2, urokinase plasminogen activator (uPA), and heat-shock protein 90α (Hsp90α) secretions are significantly decreased in TRPM7-deficient PDAC cells. Moreover, TRPM7 expression in human PDAC lymph node metastasis is correlated to the channel expression in primary tumor. Taken together, our results show that TRPM7 is involved in PDAC cell invasion through regulation of Hsp90α/uPA/MMP-2 proteolytic axis, confirming that this channel could be a promising biomarker and possibly a target for PDAC metastasis therapy.

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Section: Introductionmentioning

confidence: 99%

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

et al. 2017

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“…However, multiple studies have recently demonstrated their expression in non-excitable cells, in which they regulate cellular functions such as migration, differentiation, endosome acidification, phagocytosis and podosome formation15. In addition, Na V are abnormally expressed in carcinoma cells and tumour biopsies, and their activity is associated with aggressive features and cancer progression161718. Expression of the Na V 1.5 isoform in breast tumours is correlated with metastases development and patients' death1920.…”

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confidence: 99%

SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer

et al. 2016

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The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed ‘mesenchymal' and ‘amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (NaV) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid–mesenchymal hybrid phenotype. This hyperactivated migration is independent of NaV and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene.

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“…TTX, tetrodotoxin sensitive; SCN5A, gene that encodes Na v 1.5; SCN9A, gene that encodes Na v 1.7; VGSCs, voltage-gated sodium channels. Source: Besson et al (2015), Driffort et al (2014), Nelson, Yang, Dowle, Thomas, and Brackenbury (2015), Patel and Brackenbury (2015), and Roger et al (2015).…”

Section: Human-sw480mentioning

confidence: 98%

Sodium Channels in Pain and Cancer

Luiz

Wood

2016

Advances in Pharmacology

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How do voltage-gated sodium channels enhance migration and invasiveness in cancer cells?

Cited by 89 publications

References 93 publications

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway

SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer

Sodium Channels in Pain and Cancer

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