G3BP1 is Required for the Senescence-Associated Secretory Phenotype

The senescence-associated secretory phenotype (SASP) is how senescent cells cause long-term harm. It is also how senescent cells produce short-term benefits. SASP is the name given to the mix of inflammatory signals, growth factors, and other molecules and vesicles secreted by senescent cells. This is helpful during embryonic development, as well as in wound healing and suppression of cancer. In these cases, a small number of cells become senescent in order to beneficially alter the local signaling environment to provoke immune activity, restructuring, and growth. These helpful senescent cells are soon destroyed by immune cells or via programmed cell death. We age, however, more cells become senescent in response to damage and dysfunction, and the processes of clearance become slower and less effective. Senescent cells accumulate in tissues, and a constant SASP disrupts tissue maintenance, tissue structure, and immune function, giving rise to a state of chronic inflammation.

A number of research groups are working towards ways to modulate or shut down the SASP as an alternative to periodic selective destruction of senescent cells via senolytic therapies. Today's open access paper is a promising step towards turning off the SASP entirely. The challenge inherent in this goal is similar to that in achieving immunosuppression - the SASP is both beneficial and harmful, depending on location, timing, and circumstance. Shutting it down entirely for the long term will have unfortunate side-effects. It isn't just that the SASP is involved in regeneration, but also that it enables the prompt destruction of potentially cancerous cells. Still, in cases where the SASP is raging due to the presence of significant numbers of senescent cells, and the resulting chronic inflammation and pro-growth signaling is accelerating the progression of an established cancer, then shutting down the SASP may well be a useful strategy in combination with other cancer therapies.

G3BP1 controls the senescence-associated secretome and its impact on cancer progression

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. Generally, these cells undergo profound molecular and biological changes, namely decreased genomic stability, increased markers of DNA damage, and induction of the senescent-associated secretory phenotype (SASP). The SASP is a large group of secreted factors that include cytokines, chemokines, angiogenic factors, extracellular matrix-remodeling proteases, and growth factors (e.g. IL-6, IL-8, and TNFα). Despite the protective role that senescence plays in an organism, the accumulation of senescent cells during aging has been associated with many cancers by enhancing neoplastic cell proliferation and metastasis. The most striking evidence supporting a link between senescence and cancer is the fact that removing senescent cells from mice decreases cancer occurrence throughout their lifespan.

The Ras GTPase-activating protein-binding protein 1 (G3BP1), a key factor in the stress response and stress granule (SG) assembly, is associated with several processes including pro-survival response and cell fate. G3bp1-/- mice exhibit a premature aging phenotype as well as symptoms of pathologies related to aging such as ataxia. Since the loss of G3BP1 is associated with age-related phenotypes, it is possible that G3BP1 modulates these effects by controlling cellular senescence and cancer growth.

In this study, we assessed the role of G3BP1 as a regulator of the deleterious effects of senescent cells. We show that 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.

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