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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

  • Authors:
    • Zhengzheng Xiao
    • Jing Liang
    • Qing Deng
    • Chaojun Song
    • Xiaoli Yang
    • Zebin Liu
    • Zheng Shao
    • Kun Zhang
    • Xiaobin Wang
    • Zhengwei Li
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of Pathology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Department of General Practice, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China, Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 210011, P.R. China, Department of Urology, Carson International Cancer Centre, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Centre, Shenzhen University, Shenzhen, Guangdong 518000, P.R. China, Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
    Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 113-124
    |
    Published online on: November 5, 2020
       https://doi.org/10.3892/ijmm.2020.4784
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Abstract

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.
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Copy and paste a formatted citation
Spandidos Publications style
Xiao Z, Liang J, Deng Q, Song C, Yang X, Liu Z, Shao Z, Zhang K, Wang X, Li Z, Li Z, et al: Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways. Int J Mol Med 47: 113-124, 2021.
APA
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z. ... Li, Z. (2021). Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways. International Journal of Molecular Medicine, 47, 113-124. https://doi.org/10.3892/ijmm.2020.4784
MLA
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z., Shao, Z., Zhang, K., Wang, X., Li, Z."Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways". International Journal of Molecular Medicine 47.1 (2021): 113-124.
Chicago
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z., Shao, Z., Zhang, K., Wang, X., Li, Z."Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways". International Journal of Molecular Medicine 47, no. 1 (2021): 113-124. https://doi.org/10.3892/ijmm.2020.4784
Copy and paste a formatted citation
x
Spandidos Publications style
Xiao Z, Liang J, Deng Q, Song C, Yang X, Liu Z, Shao Z, Zhang K, Wang X, Li Z, Li Z, et al: Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways. Int J Mol Med 47: 113-124, 2021.
APA
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z. ... Li, Z. (2021). Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways. International Journal of Molecular Medicine, 47, 113-124. https://doi.org/10.3892/ijmm.2020.4784
MLA
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z., Shao, Z., Zhang, K., Wang, X., Li, Z."Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways". International Journal of Molecular Medicine 47.1 (2021): 113-124.
Chicago
Xiao, Z., Liang, J., Deng, Q., Song, C., Yang, X., Liu, Z., Shao, Z., Zhang, K., Wang, X., Li, Z."Pimozide augments bromocriptine lethality in prolactinoma cells and in a xenograft model via the STAT5/cyclin D1 and STAT5/Bcl‑xL signaling pathways". International Journal of Molecular Medicine 47, no. 1 (2021): 113-124. https://doi.org/10.3892/ijmm.2020.4784
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