Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype
The P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/21/8177 |
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| author | Nataša Pavlović Maria Kopsida Pär Gerwins Femke Heindryckx |
| author_facet | Nataša Pavlović Maria Kopsida Pär Gerwins Femke Heindryckx |
| author_sort | Nataša Pavlović |
| collection | DOAJ |
| description | The P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 is expressed by macrophages in the liver. Using in vitro methods, we show that inhibition of P2Y12 with ticagrelor enhances tumor cell phagocytosis by macrophages and induces an anti-tumoral phenotype. Treatment with ticagrelor also increases the expression of several actors of the endoplasmic reticulum (ER) stress pathways, suggesting activation of the unfolded protein response (UPR). Inhibiting the UPR with tauroursodeoxycholic acid (Tudca) diminishes the pro-phagocytotic effect of ticagrelor, thereby indicating that P2Y12 mediates macrophage function through activation of ER stress pathways. This could be relevant in the pathogenesis of chronic liver disease and cancer, as macrophages are considered key players in these inflammation-driven pathologies. |
| first_indexed | 2024-03-10T15:10:03Z |
| format | Article |
| id | doaj.art-d61ef87657334e10a051e021edce58c3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:10:03Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d61ef87657334e10a051e021edce58c32023-11-20T19:25:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012121817710.3390/ijms21218177Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral PhenotypeNataša Pavlović0Maria Kopsida1Pär Gerwins2Femke Heindryckx3Medical Cell Biology, Uppsala University, 75123 Uppsala, SwedenMedical Cell Biology, Uppsala University, 75123 Uppsala, SwedenMedical Cell Biology, Uppsala University, 75123 Uppsala, SwedenMedical Cell Biology, Uppsala University, 75123 Uppsala, SwedenThe P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 is expressed by macrophages in the liver. Using in vitro methods, we show that inhibition of P2Y12 with ticagrelor enhances tumor cell phagocytosis by macrophages and induces an anti-tumoral phenotype. Treatment with ticagrelor also increases the expression of several actors of the endoplasmic reticulum (ER) stress pathways, suggesting activation of the unfolded protein response (UPR). Inhibiting the UPR with tauroursodeoxycholic acid (Tudca) diminishes the pro-phagocytotic effect of ticagrelor, thereby indicating that P2Y12 mediates macrophage function through activation of ER stress pathways. This could be relevant in the pathogenesis of chronic liver disease and cancer, as macrophages are considered key players in these inflammation-driven pathologies.https://www.mdpi.com/1422-0067/21/21/8177inflammationpurinergic receptorsmacrophagesliver diseasecancer |
| spellingShingle | Nataša Pavlović Maria Kopsida Pär Gerwins Femke Heindryckx Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype International Journal of Molecular Sciences inflammation purinergic receptors macrophages liver disease cancer |
| title | Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype |
| title_full | Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype |
| title_fullStr | Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype |
| title_full_unstemmed | Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype |
| title_short | Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype |
| title_sort | inhibiting p2y12 in macrophages induces endoplasmic reticulum stress and promotes an anti tumoral phenotype |
| topic | inflammation purinergic receptors macrophages liver disease cancer |
| url | https://www.mdpi.com/1422-0067/21/21/8177 |
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