Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells
The present study was designed to evaluate how estradiol alone or in combination with G protein-coupled estrogen receptor (GPER) agonists and GPER and peroxisome proliferator-activated receptor (PPAR) antagonists alter the expression of tumor growth factor β (TGF-β), cyclooxygenase-2 (COX-2), hypoxi...
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MDPI AG
2022-06-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/6/1390 |
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| author | Ewelina Gorowska-Wojtowicz Michal Duliban Malgorzata Kotula-Balak Barbara Bilinska |
| author_facet | Ewelina Gorowska-Wojtowicz Michal Duliban Malgorzata Kotula-Balak Barbara Bilinska |
| author_sort | Ewelina Gorowska-Wojtowicz |
| collection | DOAJ |
| description | The present study was designed to evaluate how estradiol alone or in combination with G protein-coupled estrogen receptor (GPER) agonists and GPER and peroxisome proliferator-activated receptor (PPAR) antagonists alter the expression of tumor growth factor β (TGF-β), cyclooxygenase-2 (COX-2), hypoxia inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) in mouse testis explants and MA-10 mouse tumor Leydig cells. In order to define the hormone-associated signaling pathway, the expression of MAPK and PI3K/Akt was also examined. Tissue explants and cells were treated with estradiol as well as GPER agonist (ICI 182,780), GPER antagonist (G-15), PPARα antagonist (GW6471), and PPARγ antagonist (T00709072) in various combinations. First, we showed that in testis explants GPER and PPARα expressions were activated by the GPER agonist and estradiol (either alone or in mixtures), whereas PPARγ expression was activated only by GPER agonist. Second, increased TGF-β expression and decreased COX-2 expression were found in all experimental groups of testicular explants and MA-10 cells, except for up-regulated COX-2 expression in estradiol-treated cells, compared to respective controls. Third, estradiol treatment led to elevated expression of HIF-1α and VEGF, while their lower levels versus control were noted in the remaining groups of explants. Finally, we demonstrated the up-regulation of MAPK and PI3Kp85/Akt expressions in estradiol-treated groups of both ex vivo and in vitro models, whereas estradiol in mixtures with compounds of agonistic or antagonistic properties either up-regulated or down-regulated signaling kinase expression levels. Our results suggest that a balanced estrogen level and its action together with proper GPER and PPAR signaling play a key role in the maintenance of testis homeostasis. Moreover, changes in TGF-β and COX-2 expressions (that disrupted estrogen pathway) as well as disturbed GPER-PPAR signaling observed after estradiol treatment may be involved in testicular tumorigenesis. |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T00:20:12Z |
| publishDate | 2022-06-01 |
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| spelling | doaj.art-c4d9074c06324c9f92c5a58ecf4e9df92023-11-23T15:44:00ZengMDPI AGBiomedicines2227-90592022-06-01106139010.3390/biomedicines10061390Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig CellsEwelina Gorowska-Wojtowicz0Michal Duliban1Malgorzata Kotula-Balak2Barbara Bilinska3Department of Medical Physiology, Jagiellonian University Medical College, Michalowskiego 12, 31-126 Krakow, PolandDepartment of Endocrinology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, PolandUniversity Centre of Veterinary Medicine, University of Agriculture in Krakow, Mickiewicza 24/28, 30-059 Krakow, PolandDepartment of Endocrinology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Gronostajowa 9, 30-387 Krakow, PolandThe present study was designed to evaluate how estradiol alone or in combination with G protein-coupled estrogen receptor (GPER) agonists and GPER and peroxisome proliferator-activated receptor (PPAR) antagonists alter the expression of tumor growth factor β (TGF-β), cyclooxygenase-2 (COX-2), hypoxia inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) in mouse testis explants and MA-10 mouse tumor Leydig cells. In order to define the hormone-associated signaling pathway, the expression of MAPK and PI3K/Akt was also examined. Tissue explants and cells were treated with estradiol as well as GPER agonist (ICI 182,780), GPER antagonist (G-15), PPARα antagonist (GW6471), and PPARγ antagonist (T00709072) in various combinations. First, we showed that in testis explants GPER and PPARα expressions were activated by the GPER agonist and estradiol (either alone or in mixtures), whereas PPARγ expression was activated only by GPER agonist. Second, increased TGF-β expression and decreased COX-2 expression were found in all experimental groups of testicular explants and MA-10 cells, except for up-regulated COX-2 expression in estradiol-treated cells, compared to respective controls. Third, estradiol treatment led to elevated expression of HIF-1α and VEGF, while their lower levels versus control were noted in the remaining groups of explants. Finally, we demonstrated the up-regulation of MAPK and PI3Kp85/Akt expressions in estradiol-treated groups of both ex vivo and in vitro models, whereas estradiol in mixtures with compounds of agonistic or antagonistic properties either up-regulated or down-regulated signaling kinase expression levels. Our results suggest that a balanced estrogen level and its action together with proper GPER and PPAR signaling play a key role in the maintenance of testis homeostasis. Moreover, changes in TGF-β and COX-2 expressions (that disrupted estrogen pathway) as well as disturbed GPER-PPAR signaling observed after estradiol treatment may be involved in testicular tumorigenesis.https://www.mdpi.com/2227-9059/10/6/1390testisLeydig cellsestrogensG protein-coupled estrogen receptor (GPER)peroxisome proliferator-activated receptors (PPARs)GPER agonist/antagonist |
| spellingShingle | Ewelina Gorowska-Wojtowicz Michal Duliban Malgorzata Kotula-Balak Barbara Bilinska Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells Biomedicines testis Leydig cells estrogens G protein-coupled estrogen receptor (GPER) peroxisome proliferator-activated receptors (PPARs) GPER agonist/antagonist |
| title | Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells |
| title_full | Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells |
| title_fullStr | Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells |
| title_full_unstemmed | Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells |
| title_short | Modulatory Effects of Estradiol and Its Mixtures with Ligands of GPER and PPAR on MAPK and PI3K/Akt Signaling Pathways and Tumorigenic Factors in Mouse Testis Explants and Mouse Tumor Leydig Cells |
| title_sort | modulatory effects of estradiol and its mixtures with ligands of gper and ppar on mapk and pi3k akt signaling pathways and tumorigenic factors in mouse testis explants and mouse tumor leydig cells |
| topic | testis Leydig cells estrogens G protein-coupled estrogen receptor (GPER) peroxisome proliferator-activated receptors (PPARs) GPER agonist/antagonist |
| url | https://www.mdpi.com/2227-9059/10/6/1390 |
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