The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas
Abstract Background Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it i...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-11-01
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| Series: | BMC Endocrine Disorders |
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| Online Access: | https://doi.org/10.1186/s12902-021-00900-9 |
| _version_ | 1818683406159970304 |
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| author | Shuman Wang Aihua Wang Yu Zhang Kejing Zhu Xiong Wang Yonggang Chen Jinhu Wu |
| author_facet | Shuman Wang Aihua Wang Yu Zhang Kejing Zhu Xiong Wang Yonggang Chen Jinhu Wu |
| author_sort | Shuman Wang |
| collection | DOAJ |
| description | Abstract Background Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it is urgent to explore the molecular mechanism of bromocriptine resistance in prolactinomas. Activation of the P38 MAPK pathway affects multidrug resistance in tumours. Our previous studies have demonstrated that inhibiting MAPK14 can suppress the occurrence of prolactinoma, but the role of MAPK11/12/13/14 (p38 MAPK) signalling in dopamine agonist-resistant prolactinomas is still unclear. Methods A prolactinoma rat model was established to determine the effect of bromocriptine on MAPK11/12/13/14 signalling. DA-resistant GH3 cells and DA-sensitive MMQ cells were used, and the role of MAPK11/12/13/14 in bromocriptine-resistant prolactinomas was preliminarily verified by western blot, RT-qPCR, ELISA, flow cytometry and CCK-8 experiments. The effects of MAPK11 or MAPK14 on bromocriptine-resistant prolactinomas were further verified by siRNA transfection experiments. Results Bromocriptine was used to treat rat prolactinoma by upregulating DRD2 expression and downregulating the expression level of MAPK11/12/13/14 in vivo experiments. The in vitro experiments showed that GH3 cells are resistant to bromocriptine and that MMQ cells are sensitive to bromocriptine. Bromocriptine could significantly reduce the expression of MAPK12 and MAPK13 in GH3 cells and MMQ cells. Bromocriptine could significantly reduce the expression of MAPK11, MAPK14, NF-κB p65 and Bcl2 in MMQ but had no effect on MAPK11, MAPK14, NF-κB p65 and Bcl2 in GH3 cells. In addition, knockdown of MAPK11 and MAPK14 in GH3 cells by siRNA transfection reversed the resistance of GH3 cells to bromocriptine, and haloperidol (HAL) blocked the inhibitory effect of bromocriptine on MAPK14, MAPK11, and PRL in MMQ cells. Our findings show that MAPK11 and MAPK14 proteins are involved in bromocriptine resistance in prolactinomas. Conclusion Bromocriptine reduces the expression of MAPK11/12/13/14 in prolactinomas, and MAPK11 and MAPK14 are involved in bromocriptine resistance in prolactinomas by regulating apoptosis. Reducing the expression of MAPK11 or MAPK14 can reverse bromocriptine resistance in prolactinomas. |
| first_indexed | 2024-12-17T10:34:14Z |
| format | Article |
| id | doaj.art-153f41d5a590442696c639e7294f4b90 |
| institution | Directory Open Access Journal |
| issn | 1472-6823 |
| language | English |
| last_indexed | 2024-12-17T10:34:14Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
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| series | BMC Endocrine Disorders |
| spelling | doaj.art-153f41d5a590442696c639e7294f4b902022-12-21T21:52:26ZengBMCBMC Endocrine Disorders1472-68232021-11-0121111710.1186/s12902-021-00900-9The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomasShuman Wang0Aihua Wang1Yu Zhang2Kejing Zhu3Xiong Wang4Yonggang Chen5Jinhu Wu6Central lab, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanHealth Examination Center, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanCentral lab, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanCentral lab, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanCentral lab, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanDepartment of Pharmacy, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanCentral lab, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of WuhanAbstract Background Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it is urgent to explore the molecular mechanism of bromocriptine resistance in prolactinomas. Activation of the P38 MAPK pathway affects multidrug resistance in tumours. Our previous studies have demonstrated that inhibiting MAPK14 can suppress the occurrence of prolactinoma, but the role of MAPK11/12/13/14 (p38 MAPK) signalling in dopamine agonist-resistant prolactinomas is still unclear. Methods A prolactinoma rat model was established to determine the effect of bromocriptine on MAPK11/12/13/14 signalling. DA-resistant GH3 cells and DA-sensitive MMQ cells were used, and the role of MAPK11/12/13/14 in bromocriptine-resistant prolactinomas was preliminarily verified by western blot, RT-qPCR, ELISA, flow cytometry and CCK-8 experiments. The effects of MAPK11 or MAPK14 on bromocriptine-resistant prolactinomas were further verified by siRNA transfection experiments. Results Bromocriptine was used to treat rat prolactinoma by upregulating DRD2 expression and downregulating the expression level of MAPK11/12/13/14 in vivo experiments. The in vitro experiments showed that GH3 cells are resistant to bromocriptine and that MMQ cells are sensitive to bromocriptine. Bromocriptine could significantly reduce the expression of MAPK12 and MAPK13 in GH3 cells and MMQ cells. Bromocriptine could significantly reduce the expression of MAPK11, MAPK14, NF-κB p65 and Bcl2 in MMQ but had no effect on MAPK11, MAPK14, NF-κB p65 and Bcl2 in GH3 cells. In addition, knockdown of MAPK11 and MAPK14 in GH3 cells by siRNA transfection reversed the resistance of GH3 cells to bromocriptine, and haloperidol (HAL) blocked the inhibitory effect of bromocriptine on MAPK14, MAPK11, and PRL in MMQ cells. Our findings show that MAPK11 and MAPK14 proteins are involved in bromocriptine resistance in prolactinomas. Conclusion Bromocriptine reduces the expression of MAPK11/12/13/14 in prolactinomas, and MAPK11 and MAPK14 are involved in bromocriptine resistance in prolactinomas by regulating apoptosis. Reducing the expression of MAPK11 or MAPK14 can reverse bromocriptine resistance in prolactinomas.https://doi.org/10.1186/s12902-021-00900-9ProlactinomasDopamine agonistBromocriptineDrug resistanceMAPK11/12/13/14 |
| spellingShingle | Shuman Wang Aihua Wang Yu Zhang Kejing Zhu Xiong Wang Yonggang Chen Jinhu Wu The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas BMC Endocrine Disorders Prolactinomas Dopamine agonist Bromocriptine Drug resistance MAPK11/12/13/14 |
| title | The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas |
| title_full | The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas |
| title_fullStr | The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas |
| title_full_unstemmed | The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas |
| title_short | The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas |
| title_sort | role of mapk11 12 13 14 p38 mapk protein in dopamine agonist resistant prolactinomas |
| topic | Prolactinomas Dopamine agonist Bromocriptine Drug resistance MAPK11/12/13/14 |
| url | https://doi.org/10.1186/s12902-021-00900-9 |
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