Abstract
SummarySenescent 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.
Highlights
In response to cellular stress, senescence acts as an intrinsic tumor suppressor mechanism, engaging a long-term cell-cycle arrest (Hoare and Narita, 2018)
COX2 in senescence To investigate the role of COX2 in senescence, we reanalysed mRNA-sequencing data (Hoare et al, 2016) (GEO: GSE72407) from IMR90 human diploid fibroblasts (HDFs) undergoing RAS-induced senescence (RIS) or DNA damage-induced senescence (DDIS)
Utilizing the same IMR90 cells expressing a 4-hydroxytamoxifen (4-OHT)-inducible form of oncogenic HRASG12V (ER:HRASG12V), we found a significant upregulation of COX2 protein in both RIS and DDIS (Figure 1A); COX2 is upregulated in two further HDF lines undergoing RIS (Figure S1B)
Summary
In response to cellular stress, senescence acts as an intrinsic tumor suppressor mechanism, engaging a long-term cell-cycle arrest (Hoare and Narita, 2018). Critical to the tumor suppressor function of senescence is the SASP-dependent immune-mediated elimination of senescent cells, which is termed senescence surveillance. Immature myeloid cells (iMCs) are recruited in a Ccl2-dependent manner (Eggert et al, 2016) and develop into macrophages with effector functions to eliminate the senescent hepatocytes. This process can be subverted by cancer cells within the same microenvironment, preventing senescence surveillance (Eggert et al, 2016)
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