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Implication des canaux sodiques inhibés par la TTX dans l'invasivité des cellules cancéreuses

Abstract : Ionic channels are proteins embedded into the plasma membrane allowing ions to flow into or out of the cells, depending on the electrochemical gradient (see figure 1). Voltage-gated sodium channels (NaV1) are classically found in excitable cells since they are responsible for the depolarisation phase and propagation of action potentials. Tetrodotoxin (TTX), a toxin isolated from tetradontidae puffer fishes, is the reference inhibitor of NaV1 (figure 2). The involvement of ionic channels in oncogenic properties such as proliferation has been known since the 1980s but it took nearly a decade before they were explored functionally (see [1]). In 1997, the expression of functional NaV1 was observed in a human prostatic metastatic cell line [2]. Recently, the presence of the channel protein was correlated with the grade of the disease [3]. In 2003 we described for the first time the presence of a NaV1 in a human breast metastatic cancer cell line, MDA-MB-231 [4]. Later on it was shown that the channel expressed in these cells is the cardiac isoform NaV1.5 [11]. Inhibiting the channel with TTX or conversely increasing its activity with veratridine allowed the demonstration of a high correlation between the activity of the channel and the capacity of the cells to invade a Matrigel® which mimics the extracellular matrix (see figure 3). The membrane potential of breast cancer cells is located within the range -30 to -40mV. At this potential, NaV1.5 are partially open. Thus they let sodium ions enter into the cells continuously. Such a perturbation of the homeostasis of sodium could disturb intracellular pH and calcium homeostasis which in turn could modulate some proteolytic activities. Indeed, we observed that some cysteine proteases, also known as cathepsins, are regulated by functional NaV1.5 (see figure 4). Later on, it was found that NaV1.5 (foetal variant) can be observed in biopsies and this expression is correlated to the grade of the disease [9]. We also worked with the non-small lung cancer cell (NSCLC) lines A549, H23, H460 and Calu-1 and the immortalized non cancerous cell lines NL-20 and BEAS-2B [10]. We did not find any sodium current in these cells (NL-20 and BEAS-2B) nor in the weakly metastatic cell line A549. Conversely, the strongly metastatic cell lines H23, H460 and Calu-1 expressed functional NaV1. The common feature between all the cancer cells expressing functional channels is that the activity of the channels almost doubles the capacity of the cells to invade Matrigel® whatever the isoform of the functional channels.
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https://www.hal.inserm.fr/inserm-00143799
Contributor : Jean-Yves Le Guennec <>
Submitted on : Friday, April 27, 2007 - 10:29:50 AM
Last modification on : Monday, July 2, 2018 - 4:20:15 PM
Long-term archiving on: : Friday, November 25, 2016 - 3:41:47 PM

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Sébastien Roger, Pierre Besson, Philippe Bougnoux, Jean-Yves Le Guennec. Implication des canaux sodiques inhibés par la TTX dans l'invasivité des cellules cancéreuses. Toxines et cancer, Lavoisier, pp.1-8, 2006, 326p. 17x24 Broché. ⟨inserm-00143799⟩

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