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  2. COX2 regulates senescence secretome composition and senescence surveillance through PGE2

COX2 regulates senescence secretome composition and senescence surveillance through PGE2

  • Cell Rep. 2021 Mar 16;34(11):108860. doi: 10.1016/j.celrep.2021.108860.
Susana Gonçalves 1 Kelvin Yin 1 Yoko Ito 1 Adelyne Chan 1 Ioana Olan 1 Sarah Gough 1 Liam Cassidy 1 Eva Serrao 1 Stephen Smith 2 Andrew Young 1 Masashi Narita 3 Matthew Hoare 4
Affiliations

Affiliations

  • 1 CRUK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
  • 2 Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
  • 3 CRUK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-0026, Japan.
  • 4 CRUK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: [email protected].
Abstract

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.

Keywords

COX2; SASP; immune surveillance; liver; senescence.

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