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

Abstract

SummaryOncogenic 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.

Cav1.2 regulates osteogenesis of bone marrow‐derived mesenchymal stem cells via canonical Wnt pathway in age‐related osteoporosis

“…Calcium channels, which are in charge of calcium transportation into and out of cells and organelles, play an important role in aging (Surmeier, ; Warnier et al, ). In terms of bone aging, numerous studies have indicated the relationship between disruption of calcium channels and age‐related bone mass loss (Agacayak et al, ; Shimizu et al, ).…”

Redox and mTOR-dependent regulation of plasma lamellar calcium influx controls the senescence-associated secretory phenotype

“…2-APB is a broad-spectrum compound that both inhibits and activates STIM/Orai-mediated store-operated Ca 2+ entry (SOCE) channels depending on dose. 35 SKF-96365, though a SOCE inhibitor, also modulates Ca 2+ entry through certain TRPC channels. 36 Pre-treatment with SKF had no effect on extracellular Ca 2+ -mediated Ca 2+ influx in pre-senescent cells while eliciting a sustained Ca 2+ response in senescent cells (Figure 1(e) and (f)).…”

“…67,68 Recent studies have also shown the loss of the sodium channel, SCN9a, which regulates plasma membrane depolarization allows cellular escape from oncogene-induced senescence. 35 Maintenance of plasma membrane potential is reliant on coordinate regulation of numerous ion channels and together these observations suggest that the dysregulation of ion channel homeostasis impacts downstream signaling which results in the amplification of SA gene expression.mTOR signaling also contributes to regulation of TRPC6 channel expression and activity 44,69 as well as SASP gene expression. 46,70 Blocking TRPC6 can promote H 2 O 2 -mediated autophagy through activation of P13K/Akt/mTOR pathway.…”

Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging

“…Additionally, ion channels have been shown to be involved in the development of senescence. For example, expression of the sodium voltage-gated channel SCN9A maintains cellular senescence induced by oncogene expression, whereas loss of this channel allows mammary epithelial cells to escape senescence development (Warnier et al, 2018). SCN9A is upregulated in an NF-κB-dependent manner following oncogene induced senescence, and induces plasma membrane depolarisation in a manner similar to that of calcium and potassium ion channels (Wiel et al, 2014; Warnier et al, 2018).…”

“…For example, expression of the sodium voltage-gated channel SCN9A maintains cellular senescence induced by oncogene expression, whereas loss of this channel allows mammary epithelial cells to escape senescence development (Warnier et al, 2018). SCN9A is upregulated in an NF-κB-dependent manner following oncogene induced senescence, and induces plasma membrane depolarisation in a manner similar to that of calcium and potassium ion channels (Wiel et al, 2014; Warnier et al, 2018). TRP channel, TRPC5, has also been implicated in the development of senescence in mouse vascular endothelial cells in a ROS-dependent manner, with β-galactosidase staining reduced in cells lacking this gene (Li Z. et al, 2017).…”