COX2 regulates senescence secretome composition and senescence surveillance through PGE2.

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Gonçalves, Susana 
Yin, Kelvin 
Ito, Yoko 
Chan, Adelyne 

Senescent cells trigger their own immune-mediated destruction, termed senescence surveillance. This is dependent on the inflammatory senescence-associated secretory phenotype (SASP), which includes COX2, an enzyme with complex roles in cancer. The role COX2 plays during senescence surveillance is unknown. Here, we show that during RAS-induced senescence (RIS), COX2 is a critical regulator of SASP composition and senescence surveillance in vivo. COX2 regulates the expression of multiple inflammatory SASP components through an autocrine feedback loop involving its downstream product, prostaglandin E2 (PGE2), binding to EP4. During in vivo hepatocyte RIS, Cox2 is critical to tumor suppression, Cxcl1 expression, and immune-mediated senescence surveillance, partially through PGE2. Loss of Cox2 in RIS dysregulates the intrahepatic immune microenvironment, with enrichment of immunosuppressive immature myeloid cells and CD4+ regulatory T lymphocytes. Therefore, COX2 and PGE2 play a critical role in senescence, shaping SASP composition, promoting senescence surveillance and tumor suppression in the earliest stages of tumorigenesis.

COX2, SASP, immune surveillance, liver, senescence, Animals, Cellular Senescence, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Dinoprostone, Female, Fibroblasts, Humans, Mice, Inbred C57BL, Receptors, Prostaglandin E, EP4 Subtype, Secretome, Senescence-Associated Secretory Phenotype, Tumor Microenvironment, Up-Regulation
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Elsevier BV
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Cancer Research UK (CB4210)
Cancer Research UK (19924)
Medical Research Council (MR/R010013/1)
Biotechnology and Biological Sciences Research Council (BB/S013466/1)
Cancer Research UK (24453)
Cancer Research UK (A19924)
This work was supported by a CRUK Advanced Clinician Scientist Fellowship to MH (C52489/A19924) and a Cancer Research UK Cambridge Institute Core Grant (C9545/A29580) to MN. MH and MN are also supported by a Medical Research Council project grant (MR/R010013/1); MN is also supported by the Biotechnology and Biological Science Research Council (BB/S013466/1).