CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway
CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its i...
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MDPI AG
2023-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/9/1210 |
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| author | Hai-zhou Ji Li Chen Mi Ren Sang Li Tong-yu Liu Hong-ju Chen Hui-hui Yu Yang Sun |
| author_facet | Hai-zhou Ji Li Chen Mi Ren Sang Li Tong-yu Liu Hong-ju Chen Hui-hui Yu Yang Sun |
| author_sort | Hai-zhou Ji |
| collection | DOAJ |
| description | CXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-β1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of <i>SLC7A11</i> and <i>GPX4</i>. These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when <i>CXCR2</i> was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate <i>SLC7A11</i> and <i>GPX4</i> expression, protecting endothelial cells from ferroptosis. |
| first_indexed | 2024-03-10T22:17:48Z |
| format | Article |
| id | doaj.art-b3edbb989035465c8cd65cb6fed40c26 |
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| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T22:17:48Z |
| publishDate | 2023-08-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-b3edbb989035465c8cd65cb6fed40c262023-11-19T12:24:05ZengMDPI AGPharmaceuticals1424-82472023-08-01169121010.3390/ph16091210CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling PathwayHai-zhou Ji0Li Chen1Mi Ren2Sang Li3Tong-yu Liu4Hong-ju Chen5Hui-hui Yu6Yang Sun7Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Oncological Nursing, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaDepartment of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350014, ChinaCXCL8-CXCR1/CXCR2 signaling pathways might form complex crosstalk among different cell types within the ovarian tumor microenvironment, thereby modulating the behaviors of different cells. This study aimed to investigate the expression pattern of CXCL8 in the ovarian tumor microenvironment and its impact on both endothelial-to-mesenchymal transition (EndMT) and ferroptosis of endothelial cells. The human monocytic cell line THP-1 and the human umbilical vein endothelial cell line PUMC-HUVEC-T1 were used to conduct in vitro studies. Erastin was used to induce ferroptosis. Results showed that tumor-associated macrophages are the major source of CXCL8 in the tumor microenvironment. CXCL8 treatment promoted the nucleus entrance of NF-κB p65 and p65 phosphorylation via CXCR2 in endothelial cells, suggesting activated NF-κB signaling. Via the NF-κB signaling pathway, CXCL8 enhanced TGF-β1-induced EndMT of PUMC-HUVEC-T1 cells and elevated their expression of <i>SLC7A11</i> and <i>GPX4</i>. These trends were drastically weakened in groups with CXCR2 knockdown or SB225002 treatment. TPCA-1 reversed CXCL8-induced upregulation of SLC7A11 and GPX4. CXCL8 protected endothelial cells from erastin-induced ferroptosis. However, these protective effects were largely canceled when <i>CXCR2</i> was knocked down. In summary, CXCL8 can activate the NF-κB signaling pathway in endothelial cells in a CXCR2-dependent manner. The CXCL8-CXCR2/NF-κB axis can enhance EndMT and activate <i>SLC7A11</i> and <i>GPX4</i> expression, protecting endothelial cells from ferroptosis.https://www.mdpi.com/1424-8247/16/9/1210CXCL8CXCR2NF-κBferroptosisendothelial cells |
| spellingShingle | Hai-zhou Ji Li Chen Mi Ren Sang Li Tong-yu Liu Hong-ju Chen Hui-hui Yu Yang Sun CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway Pharmaceuticals CXCL8 CXCR2 NF-κB ferroptosis endothelial cells |
| title | CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway |
| title_full | CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway |
| title_fullStr | CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway |
| title_full_unstemmed | CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway |
| title_short | CXCL8 Promotes Endothelial-to-Mesenchymal Transition of Endothelial Cells and Protects Cells from Erastin-Induced Ferroptosis via CXCR2-Mediated Activation of the NF-κB Signaling Pathway |
| title_sort | cxcl8 promotes endothelial to mesenchymal transition of endothelial cells and protects cells from erastin induced ferroptosis via cxcr2 mediated activation of the nf κb signaling pathway |
| topic | CXCL8 CXCR2 NF-κB ferroptosis endothelial cells |
| url | https://www.mdpi.com/1424-8247/16/9/1210 |
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