Abstract
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the BCL2 family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.
Highlights
Senescence was originally identified through the limited ability of primary fibroblasts in culture to undergo cell division
A Reporter-Based CRISPR Screen for SenescenceInducing Genes Kang et al (2015) recently demonstrated that human primary fibroblasts strongly upregulate the expression of microRNA 146a during the process of senescence, irrespective of how senescence was induced
They demonstrated that a reporter construct in which the promoter of microRNA 146a (miR146a) was linked to EGFP was activated during induction of senescence
Summary
Senescence was originally identified through the limited ability of primary fibroblasts in culture to undergo cell division. Senescence is generally considered to be a fail-safe mechanism against oncogenic transformation, as expression of an oncogenic RAS gene in primary cells leads to the rapid induction of a post-replicative state referred to as oncogene-induced senescence (OIS) (Serrano et al, 1997). This fail-safe mechanism operates in humans to prevent cancer, as melanocytic nevi (moles) often carry an activated BRAF(V600E) oncogene, but stain for many of the senescence markers, indicative of a stable and lasting state of oncogeneinduced senescence in these cells (Michaloglou et al, 2005). Even some advanced cancer cells can be induced to enter a state of senescence, as a result of chemotherapy treatment and by excessive oncogenic signaling (Ewald et al, 2010; Sun et al, 2014)
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