TY - JOUR
T1 - G3BP1 controls the senescence-associated secretome and its impact on cancer progression
AU - Omer, Amr
AU - Barrera, Monica Cruz
AU - Moran, Julian L.
AU - Lian, Xian J.
AU - Di Marco, Sergio
AU - Beausejour, Christian
AU - Gallouzi, Imed Eddine
N1 - Generated from Scopus record by KAUST IRTS on 2022-09-13
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.nature.com/articles/s41467-020-18734-9
UR - http://www.scopus.com/inward/record.url?scp=85091964751&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-18734-9
DO - 10.1038/s41467-020-18734-9
M3 - Article
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -