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Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways
As hyperprolactinemia is observed in patients with bromocriptine-resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase-2 (JAK2)/signal transducer and activator of...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723514/ https://www.ncbi.nlm.nih.gov/pubmed/33155660 http://dx.doi.org/10.3892/ijmm.2020.4784 |
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author | Xiao, Zhengzheng Liang, Jing Deng, Qing Song, Chaojun Yang, Xiaoli Liu, Zebin Shao, Zheng Zhang, Kun Wang, Xiaobin Li, Zhengwei |
author_facet | Xiao, Zhengzheng Liang, Jing Deng, Qing Song, Chaojun Yang, Xiaoli Liu, Zebin Shao, Zheng Zhang, Kun Wang, Xiaobin Li, Zhengwei |
author_sort | Xiao, Zhengzheng |
collection | PubMed |
description | As hyperprolactinemia is observed in patients with bromocriptine-resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine-resistant prolactinoma cells. A reduction in phospho-STAT5, cyclin D1 and B-cell lymphoma extra-large (Bcl-xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem-like cells, and reduced the protein expression of the cancer stem cell markers, CD133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5-knockdown primary culture cells of human bromocriptine-resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. Collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl-xL and STAT5/cyclin D1 signaling pathways. |
format | Online Article Text |
id | pubmed-7723514 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-77235142020-12-23 Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways Xiao, Zhengzheng Liang, Jing Deng, Qing Song, Chaojun Yang, Xiaoli Liu, Zebin Shao, Zheng Zhang, Kun Wang, Xiaobin Li, Zhengwei Int J Mol Med Articles As hyperprolactinemia is observed in patients with bromocriptine-resistant prolactinoma, prolactin (PRL) has been implicated in the development of bromocriptine resistance. Since PRL primarily mediates cell survival and drug resistance via the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 5A (STAT5) signaling pathway, the STAT5 inhibitor, pimozide, may inhibit cell proliferation and reverse bromocriptine resistance in prolactinoma cells. In the present study, compared with bromocriptine or pimozide alone, the combination of pimozide and bromocriptine exerted enhanced reduction in cell growth and proliferation, and increased apoptosis and cell cycle arrest in bromocriptine-resistant prolactinoma cells. A reduction in phospho-STAT5, cyclin D1 and B-cell lymphoma extra-large (Bcl-xL) expression levels were observed in cells treated with the combination of drugs. In addition, pimozide suppressed spheroid formation of human pituitary adenoma stem-like cells, and reduced the protein expression of the cancer stem cell markers, CD133 and nestin. Pimozide did not exert any additional antitumor activity in STAT5-knockdown primary culture cells of human bromocriptine-resistant prolactinomas. Furthermore, Pimozide combined with bromocriptine treatment significantly reduced human prolactinoma xenograft growth. Western blot and immunohistochemical analyses also demonstrated significant inhibition of cell proliferation and stem cell marker proteins in vivo. Collectively, these data indicated that pimozide treatment reduced prolactinoma growth by targeting both proliferating cells and stem cells, at least in part, by inhibiting the STAT5/Bcl-xL and STAT5/cyclin D1 signaling pathways. D.A. Spandidos 2021-01 2020-11-05 /pmc/articles/PMC7723514/ /pubmed/33155660 http://dx.doi.org/10.3892/ijmm.2020.4784 Text en Copyright: © Xiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Xiao, Zhengzheng Liang, Jing Deng, Qing Song, Chaojun Yang, Xiaoli Liu, Zebin Shao, Zheng Zhang, Kun Wang, Xiaobin Li, Zhengwei Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title | Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title_full | Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title_fullStr | Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title_full_unstemmed | Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title_short | Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl-xL signaling pathways |
title_sort | pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the stat5/cyclin d1 and stat5/bcl-xl signaling pathways |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723514/ https://www.ncbi.nlm.nih.gov/pubmed/33155660 http://dx.doi.org/10.3892/ijmm.2020.4784 |
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