Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression
Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor...
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| Format: | Article |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.985618/full |
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| author | Ming Yu Ming Yu Ming Yu Yali Yang Yali Yang Yali Yang Yali Yang Hao Zhao Mengxia Li Mengxia Li Mengxia Li Jie Chen Jie Chen Jie Chen Baobei Wang Baobei Wang Baobei Wang Tianxia Xiao Tianxia Xiao Tianxia Xiao Chen Huang Chen Huang Chen Huang Huashan Zhao Huashan Zhao Huashan Zhao Wei Zhou Jian V. Zhang Jian V. Zhang Jian V. Zhang |
| author_facet | Ming Yu Ming Yu Ming Yu Yali Yang Yali Yang Yali Yang Yali Yang Hao Zhao Mengxia Li Mengxia Li Mengxia Li Jie Chen Jie Chen Jie Chen Baobei Wang Baobei Wang Baobei Wang Tianxia Xiao Tianxia Xiao Tianxia Xiao Chen Huang Chen Huang Chen Huang Huashan Zhao Huashan Zhao Huashan Zhao Wei Zhou Jian V. Zhang Jian V. Zhang Jian V. Zhang |
| author_sort | Ming Yu |
| collection | DOAJ |
| description | Endometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention. |
| first_indexed | 2024-04-12T06:19:21Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T06:19:21Z |
| publishDate | 2022-11-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-82d00d26041749879746583196008e002022-12-22T03:44:22ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.985618985618Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progressionMing Yu0Ming Yu1Ming Yu2Yali Yang3Yali Yang4Yali Yang5Yali Yang6Hao Zhao7Mengxia Li8Mengxia Li9Mengxia Li10Jie Chen11Jie Chen12Jie Chen13Baobei Wang14Baobei Wang15Baobei Wang16Tianxia Xiao17Tianxia Xiao18Tianxia Xiao19Chen Huang20Chen Huang21Chen Huang22Huashan Zhao23Huashan Zhao24Huashan Zhao25Wei Zhou26Jian V. Zhang27Jian V. Zhang28Jian V. Zhang29Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaShenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen, ChinaCollege of Life Science, Northeast Forestry University, Harbin, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaHuazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, ChinaCenter for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, ChinaShenzhen Key Laboratory of Metabolic Health, Shenzhen, ChinaEndometriosis is a common gynecological disease, characterized by the presence of endometrial-like lesions outside the uterus. This debilitating disease causes chronic pelvic pain and infertility with limited therapeutics. Chemerin is a secretory protein that acts on CMKLR1 (Chemokine-Like Receptor 1) to execute functions vital for immunity, adiposity, and metabolism. Abnormal chemerin/CMKLR1 axis underlies the pathological mechanisms of certain diseases including cancer and inflammatory diseases, but its role in endometriosis remains unknown. Herein, our results showed that chemerin and CMKLR1 are up-regulated in endometriotic lesions by analyzing the human endometriosis database and murine model. Knockdown of chemerin or CMKLR1 by shRNA led to mesenchymal-epithelial transition (MET) along with compromised viability, migration, and invasion of hEM15A cells. Most importantly, 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA), a small molecule antagonist for CMKLR1, was evidenced to exhibit profound anti-endometriosis effects (anti-growth, anti-mesenchymal features, anti-angiogenesis, and anti-inflammation) in vitro and in vivo. Mechanistically, α-NETA exhibited a dual inhibition effect on PI3K/Akt and MAPK/ERK signaling pathways in hEM15A cells and murine endometriotic grafts. This study highlights that the chemerin/CMKLR1 signaling axis is critical for endometriosis progression, and targeting this axis by α-NETA may provide new options for therapeutic intervention.https://www.frontiersin.org/articles/10.3389/fphar.2022.985618/fullendometriosischemerinCMKLR1small molecule antagonistα-NETA |
| spellingShingle | Ming Yu Ming Yu Ming Yu Yali Yang Yali Yang Yali Yang Yali Yang Hao Zhao Mengxia Li Mengxia Li Mengxia Li Jie Chen Jie Chen Jie Chen Baobei Wang Baobei Wang Baobei Wang Tianxia Xiao Tianxia Xiao Tianxia Xiao Chen Huang Chen Huang Chen Huang Huashan Zhao Huashan Zhao Huashan Zhao Wei Zhou Jian V. Zhang Jian V. Zhang Jian V. Zhang Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression Frontiers in Pharmacology endometriosis chemerin CMKLR1 small molecule antagonist α-NETA |
| title | Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression |
| title_full | Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression |
| title_fullStr | Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression |
| title_full_unstemmed | Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression |
| title_short | Targeting the chemerin/CMKLR1 axis by small molecule antagonist α-NETA mitigates endometriosis progression |
| title_sort | targeting the chemerin cmklr1 axis by small molecule antagonist α neta mitigates endometriosis progression |
| topic | endometriosis chemerin CMKLR1 small molecule antagonist α-NETA |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.985618/full |
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