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

ABSTRACT: Oncogenic signals can induce premature senescence (OIS) in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A sodium channel allowed cells to escape from OIS. Here we studied the transcriptome profiles of an OIS model based on human mammary epithelial cells stably expressing hTert to be immortalized and MEK:ER, a 4-hydroxytamoxifen (4-OHT) inducible oncogene MEK:ER (HEC-TM cells), to induce the oncogenic signal. We used an shRNA in order to knockdown SCN9A expression during OIS, and KCL treatment to study the impact of membrane depolarization on senescence induction. We showed that SCN9A and plama 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 NFkB transcription factor, SCN9A expression, plasma membrane depolarization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110884 | GEO | 2018/02/21

REPOSITORIES: GEO

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Project description:This experiment was designed to study oncogene-induced senescence (OIS). To this end we generated a series of cell lines derived from normal human diploid fibroblasts IMR90 forced to express the catalytic subunit of telomerase (hTERT). This cells were then subjected to further manipulation by orderly introducing defined genetic elements by retroviral transduction. The first cell line generated was ITV, which was obtained from the original cell line (IMR90 with hTERT) after introducing an empty vector. Subsequently, we introduced Mek:ER, which is a switchable version of the Mek kinase, a relevant downstream effector of Ras signaling during Ras-induced senescence, to generate ITM cells. We further modified this cell line by introducing SV40 small-t antigen (ST), papillomavirus oncoproteins E6 and E7 (E6/E7) or the combination of both (E6/E7 and ST). In this manner, we obtained ITMST, ITME6E7 and ITME6E7ST respectively. This cellular system allow us to have a representation of the different steps into neoplastic transformation. ITM and ITMST cells respond to Mek activation by inducing OIS. ITME6E7 and ITME6E7ST cells do not enter OIS after Mek activation. Mek activation is achieved by treating all cell cultures with 4-hydroxytamoxifen (4OHT) at 100 nM, in the absence of serum, and for 3 days. The gene expression profile of ITV cells served as a reference for all the expression values obtained with the rest of the cell lines. Thus, we ended up with the expression profiles of two cell lines representing oncogene-induced senescence (ITM and ITMST), and two cell lines representing bypass of oncogene-induced senescence, plus a reference profile provided by ITV, the cell line from which all the other cell lines were derived. Our final goal was to identify markers of the oncogene-induced senescence response by comparing the expression profiles of the cell lines entering OIS after Mek activation (that is, after 4OHT treatment) with the ones bypassing this response. Keywords: other

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

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