COX2 regulates senescence secretome composition and senescence surveillance through PGE2
| Autor: | Susana Gonçalves, Kelvin Yin, Sarah Gough, Yoko Ito, Liam D. Cassidy, Ioana Olan, Stephen Smith, Masashi Narita, Adelyne S. L. Chan, Matthew Hoare, Andrew R. J. Young, Eva M. Serrao |
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| Přispěvatelé: | Olan, Ioana [0000-0003-0692-1831], Smith, Stephen [0000-0001-7744-3238], Young, Andrew [0000-0002-7522-5525], Narita, Masashi [0000-0001-7764-577X], Hoare, Matthew [0000-0001-5990-9604], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Senescence senescence Regulator macromolecular substances Biology SASP liver medicine.disease_cause Dinoprostone General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Tumor Microenvironment medicine Animals Humans Prostaglandin E2 Autocrine signalling Cellular Senescence Secretome Cyclooxygenase 2 Inhibitors immune surveillance food and beverages Fibroblasts Phenotype Up-Regulation Cell biology Mice Inbred C57BL CXCL1 030104 developmental biology medicine.anatomical_structure Cyclooxygenase 2 Hepatocyte Female Senescence-Associated Secretory Phenotype Carcinogenesis Receptors Prostaglandin E EP4 Subtype COX2 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell Reports. 34:108860 |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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