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...

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Autores principales:	Shuman Wang, Aihua Wang, Yu Zhang, Kejing Zhu, Xiong Wang, Yonggang Chen, Jinhu Wu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Prolactinomas Dopamine agonist Bromocriptine Drug resistance MAPK11/12/13/14 Diseases of the endocrine glands. Clinical endocrinology RC648-665
Acceso en línea:	https://doaj.org/article/153f41d5a590442696c639e7294f4b90
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spelling	oai:doaj.org-article:153f41d5a590442696c639e7294f4b902021-11-28T12:03:11ZThe role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas10.1186/s12902-021-00900-91472-6823https://doaj.org/article/153f41d5a590442696c639e7294f4b902021-11-01T00:00:00Zhttps://doi.org/10.1186/s12902-021-00900-9https://doaj.org/toc/1472-6823Abstract 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.Shuman WangAihua WangYu ZhangKejing ZhuXiong WangYonggang ChenJinhu WuBMCarticleProlactinomasDopamine agonistBromocriptineDrug resistanceMAPK11/12/13/14Diseases of the endocrine glands. Clinical endocrinologyRC648-665ENBMC Endocrine Disorders, Vol 21, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Prolactinomas Dopamine agonist Bromocriptine Drug resistance MAPK11/12/13/14 Diseases of the endocrine glands. Clinical endocrinology RC648-665
spellingShingle	Prolactinomas Dopamine agonist Bromocriptine Drug resistance MAPK11/12/13/14 Diseases of the endocrine glands. Clinical endocrinology RC648-665 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
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.
format	article
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
title	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_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_sort	role of mapk11/12/13/14 (p38 mapk) protein in dopamine agonist-resistant prolactinomas
publisher	BMC
publishDate	2021
url	https://doaj.org/article/153f41d5a590442696c639e7294f4b90
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_version_	1718408242410815488

The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas

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