Abstract
Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.
Highlights
Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes
The expression of bona fide markers of senescence[30] such as p21WAF1/Cip[1] or p16INK4a did not change in the absence of G3BP1 when compared to siCTL-treated cells, while G3BP1 depletion had differential effects on the phosphorylation status of RB and p53 which was dependent on cell-type or the way by which we induced senescence (Fig. 1f, Supplementary Figs. 3, 4)
Since irradiation did not induce the formation of stress granules in WI-38 fibroblast (Supplementary Fig. 5), we concluded that any effect of G3BP1 on the behavior of senescent fibroblasts, does not involve its wellknown function as a promoter of stress granule assembly[3,31,32]
Summary
Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. One of the main promoters of age-related disease, such as cancer, is cellular senescence, a process by which cells enter an irreversible cell cycle arrest in response to various stresses[8,9,10,11] These cells undergo profound molecular and biological changes, namely decreased genomic stability and chromatin organization due to a loss in Lamin B1 expression[12,13], induction of key cyclin-dependent kinase inhibitors (CDKIs) p21WAF1/Cip[1] and p16INK4a which inhibit proliferative signaling by retinoblastoma (RB) protein[8,14], increased markers of DNA damage[15,16,17] and induction of the senescent-associated secretory phenotype (SASP)[18]. We delineated the mechanism by which G3BP1 achieves this effect and we provide a proof-ofprinciple that G3BP1 could be considered as a potential drug target to alter the behavior of senescent cell in order to combat age-related disease
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call