Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway
AbstractBackground Abnormal stromal-epithelial cell communication is a pathogenic mechanism in endometriosis, and metformin can modulate it. Insulin-like growth factor binding protein-1 (IGFBP1) plays a role in endometriosis, but the exact mechanism is unknown. IGFBP1 is reportedly a downstream targ...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Obstetrics and Gynaecology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/01443615.2024.2321651 |
| _version_ | 1797266009956024320 |
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| author | Xuping Shao Changling Li Junhui Liang Li Changzhong |
| author_facet | Xuping Shao Changling Li Junhui Liang Li Changzhong |
| author_sort | Xuping Shao |
| collection | DOAJ |
| description | AbstractBackground Abnormal stromal-epithelial cell communication is a pathogenic mechanism in endometriosis, and metformin can modulate it. Insulin-like growth factor binding protein-1 (IGFBP1) plays a role in endometriosis, but the exact mechanism is unknown. IGFBP1 is reportedly a downstream target of metformin in some diseases. We aimed to investigate the role of IGFBP1 in endometriosis development, whether it is associated with abnormal communication, and whether metformin affects IGFBP1 expression.Methods Patients who underwent surgical treatment for endometriosis or other diseases were enrolled. Ten patients with ovarian-type endometriosis and eight patients each who underwent surgical treatment for other lesions with or without endometriosis were selected, and their tissues taken for cell proliferation, western blotting, polymerase chain reaction, and knockdown experiments.Results Ectopic and eutopic stromal cells (EcSCs and EuSCs) lost their ability to inhibit epithelial cell proliferation, and IGFBP1 expression was downregulated in both groups of stromal cells compared to that in normal stromal cells (NSCs; 1.09 vs. 0.25, p = .0002 1.09 vs. 0.57, p = .0029). In an EcSC IGFBP1 overexpression model, the ability of EcSCs to inhibit epithelial cell proliferation was enhanced (EdU positivity decreased from 38% to 25%, p = .0001). Furthermore, adenosine 5’-monophosphate-activated protein kinase (AMPK) phosphorylation was downregulated in EcSCs and EuSCs compared to that in NSCs (0.99 vs. 0.42, p = .0006/0.99 vs. 0.57, p = 0.0032). Treatment of EcSCs with metformin increased AMPK phosphorylation (0.47 vs. 1.04, p = .0107) while upregulating IGFBP1 expression (0.69 vs. 1.01, p = .0164), whereas pre-treatment with an AMPK phosphorylation inhibitor abrogated metformin-induced IGFBP1 upregulation.Conclusions IGFBP1 mediates aberrant stromal-epithelial communication in endometriosis. Metformin can upregulate IGFBP1 expression in EcSCs by activating AMPK, and upregulated IGFBP1 enhances the inhibition of epithelial cell proliferation. IGFBP1 is expected to be a therapeutic target for endometriosis. |
| first_indexed | 2024-04-25T00:53:53Z |
| format | Article |
| id | doaj.art-7119d2f22ad143c5b6a641652ee808ea |
| institution | Directory Open Access Journal |
| issn | 0144-3615 1364-6893 |
| language | English |
| last_indexed | 2024-04-25T00:53:53Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Obstetrics and Gynaecology |
| spelling | doaj.art-7119d2f22ad143c5b6a641652ee808ea2024-03-11T14:22:07ZengTaylor & Francis GroupJournal of Obstetrics and Gynaecology0144-36151364-68932024-12-0144110.1080/01443615.2024.2321651Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathwayXuping Shao0Changling Li1Junhui Liang2Li Changzhong3Department of Gynaecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Obstetrics and Gynecology Outpatient Clinic, the People’s Hospital of Pingyi County, Linyi, Shandong, ChinaDepartment of Gynaecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Gynaecology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaAbstractBackground Abnormal stromal-epithelial cell communication is a pathogenic mechanism in endometriosis, and metformin can modulate it. Insulin-like growth factor binding protein-1 (IGFBP1) plays a role in endometriosis, but the exact mechanism is unknown. IGFBP1 is reportedly a downstream target of metformin in some diseases. We aimed to investigate the role of IGFBP1 in endometriosis development, whether it is associated with abnormal communication, and whether metformin affects IGFBP1 expression.Methods Patients who underwent surgical treatment for endometriosis or other diseases were enrolled. Ten patients with ovarian-type endometriosis and eight patients each who underwent surgical treatment for other lesions with or without endometriosis were selected, and their tissues taken for cell proliferation, western blotting, polymerase chain reaction, and knockdown experiments.Results Ectopic and eutopic stromal cells (EcSCs and EuSCs) lost their ability to inhibit epithelial cell proliferation, and IGFBP1 expression was downregulated in both groups of stromal cells compared to that in normal stromal cells (NSCs; 1.09 vs. 0.25, p = .0002 1.09 vs. 0.57, p = .0029). In an EcSC IGFBP1 overexpression model, the ability of EcSCs to inhibit epithelial cell proliferation was enhanced (EdU positivity decreased from 38% to 25%, p = .0001). Furthermore, adenosine 5’-monophosphate-activated protein kinase (AMPK) phosphorylation was downregulated in EcSCs and EuSCs compared to that in NSCs (0.99 vs. 0.42, p = .0006/0.99 vs. 0.57, p = 0.0032). Treatment of EcSCs with metformin increased AMPK phosphorylation (0.47 vs. 1.04, p = .0107) while upregulating IGFBP1 expression (0.69 vs. 1.01, p = .0164), whereas pre-treatment with an AMPK phosphorylation inhibitor abrogated metformin-induced IGFBP1 upregulation.Conclusions IGFBP1 mediates aberrant stromal-epithelial communication in endometriosis. Metformin can upregulate IGFBP1 expression in EcSCs by activating AMPK, and upregulated IGFBP1 enhances the inhibition of epithelial cell proliferation. IGFBP1 is expected to be a therapeutic target for endometriosis.https://www.tandfonline.com/doi/10.1080/01443615.2024.2321651EndometriosismetforminAMPK-IGFBP1stromal–epithelial communicationPI3K-AKT |
| spellingShingle | Xuping Shao Changling Li Junhui Liang Li Changzhong Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway Journal of Obstetrics and Gynaecology Endometriosis metformin AMPK-IGFBP1 stromal–epithelial communication PI3K-AKT |
| title | Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway |
| title_full | Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway |
| title_fullStr | Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway |
| title_full_unstemmed | Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway |
| title_short | Metformin enhances epithelial cell growth inhibition via the protein kinase–insulin-like growth factor binding protein-1 pathway |
| title_sort | metformin enhances epithelial cell growth inhibition via the protein kinase insulin like growth factor binding protein 1 pathway |
| topic | Endometriosis metformin AMPK-IGFBP1 stromal–epithelial communication PI3K-AKT |
| url | https://www.tandfonline.com/doi/10.1080/01443615.2024.2321651 |
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