Research Article: The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

Date Published: February 15, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Marine Warnier, Jean‐Michel Flaman, Christophe Chouabe, Clotilde Wiel, Baptiste Gras, Audrey Griveau, Elena Blanc, Jean‐Philippe Foy, Pauline Mathot, Pierre Saintigny, Fabien Van Coppenolle, David Vindrieux, Nadine Martin, David Bernard.


Oncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene‐induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss‐of‐function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF‐κB transcription factors, which are well‐known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NF‐κB transcription factor, SCN9A expression, plasma membrane depolarization, increased calcium, the Rb/E2F pathway and mitotic gene repression in the regulation of senescence. This work thus provides new insight into the involvement of ion channels and plasma membrane potential in the control of senescence.

Partial Text

A state of senescence is mainly characterized by a stable proliferation arrest, the acquisition of a senescence‐associated secretory programme (SASP), and a senescence‐associated β‐galactosidase activity (SA‐β‐Gal). Normal human cells enter into a state of senescence in response to numerous stresses, such as oncogenic signals, short telomeres, genotoxic or oxidative stresses. Senescence is a protective mechanism against tumor development, as it avoids cell division and it allows the elimination of potentially harmful cells by the immune system, through the SASP (Adams, 2009; Collado & Serrano, 2010; Kang et al., 2011).

Using a loss‐of‐function genetic screen, we identified the SCN9A sodium channel, a gene frequently repressed in tumors, as a pro‐senescence gene, as its knockdown enabled OIS escape. Interestingly, SCN9A levels were upregulated during OIS by the NF‐κB transcription factors. Indeed, we demonstrated that inhibition of NF‐κB transcription factors, either by the constitutive expression of a stabilized IKBA, an endogenous NF‐κB inhibitor, or by knocking down RELA, the main NF‐κB member, suppresses oncogenic stress‐induced SNC9A expression.

None declared.

MW, JMF, NM, and DB designed research; MW, JMF, CC, DV, CW, BG, EB, PM, FVC, AG and PS performed research; MW, JMF, CC, CW, BG, DV, and JPF analyzed data; MW, JMF, and DB wrote the article; and DB supervised the all research.




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