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Updated: Feb 14, 2026
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway
Marine Warnier1, Jean-Michel Flaman1, Christophe Chouabe2
1Inserm U1052, CNRS UMR 5286, Université de Lyon & Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Abstract:
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.
Insights
Loss of SCN9A prevents oncogene-induced senescence (OIS). SCN9A upregulation and plasma membrane depolarization trigger OIS by repressing mitotic genes via a calcium/Rb/E2F pathway, revealing a novel senescence regulatory mechanism.
Area of Science:
- Cellular senescence
- Cancer biology
- Ion channel function
Background:
- Oncogene-induced senescence (OIS) is a crucial tumor suppression mechanism that halts proliferation of abnormal cells.
- Identifying novel regulators of OIS is essential for understanding cancer prevention and developing new therapeutic strategies.
Purpose of the Study:
- To identify novel regulators of oncogene-induced senescence (OIS).
- To elucidate the role of the sodium channel SCN9A in OIS.
- To uncover the molecular pathway linking SCN9A to senescence.
Main Methods:
- Loss-of-function genetic screen to identify OIS regulators.
- Analysis of SCN9A expression in senescent cells.
- Investigation of NF-κB involvement in SCN9A upregulation.
- Assessment of plasma membrane potential changes upon SCN9A induction.
- Computational and experimental analysis of the calcium/Rb/E2F pathway.
Main Results:
- Loss of SCN9A enabled cells to escape OIS.
- SCN9A expression increased in senescent cells, mediated by NF-κB.
- SCN9A induction caused plasma membrane depolarization and premature senescence.
- SCN9A and membrane depolarization repressed mitotic genes via the calcium/Rb/E2F pathway, promoting senescence.
Conclusions:
- SCN9A is a novel regulator of OIS.
- A new pathway involving NF-κB, SCN9A, membrane depolarization, calcium signaling, and the Rb/E2F pathway controls senescence.
- Ion channels and plasma membrane potential play a significant role in regulating senescence.
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