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

doi:10.3892/ijmm.2020.4784

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
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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
Published online on: November 5, 2020 https://doi.org/10.3892/ijmm.2020.4784
Pages: 113-124
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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1	Mete O, Cintosun A, Pressman I and Asa SL: Epidemiology and biomarker profile of pituitary adenohypophysial tumors. Mod Pathol. 31:900–909. 2018. View Article : Google Scholar : PubMed/NCBI
2	Liu J, He Y, Zhang X, Yan X and Huang Y: Clinicopathological analysis of 250 cases of pituitary adenoma under the new WHO classification. Oncol Lett. 19:1890–1898. 2020.PubMed/NCBI
3	Lim CT and Korbonits M: Update on the clinicopathology of pituitary adenomas. Endocr Pract. 24:473–488. 2018. View Article : Google Scholar : PubMed/NCBI
4	Tang C, Sun R, Wen G, Zhong C, Yang J, Zhu J, Cong Z, Luo X and Ma C: Bromocriptine and cabergoline induce cell death in prolactinoma cells via the ERK/EGR1 and AKT/mTOR pathway respectively. Cell Death Dis. 10:3352019. View Article : Google Scholar : PubMed/NCBI
5	Molitch ME: Pharmacologic resistance in prolactinoma patients. Pituitary. 8:43–52. 2005. View Article : Google Scholar
6	Kavarthapu R and Dufau ML: Essential role of endogenous prolactin and CDK7 in estrogen-induced upregulation of the prolactin receptor in breast cancer cells. Oncotarget. 8:27353–27363. 2017. View Article : Google Scholar : PubMed/NCBI
7	Clevenger CV, Gadd SL and Zheng J: New mechanisms for PRLr action in breast cancer. Trends Endocrinol Metab. 20:223–229. 2009. View Article : Google Scholar : PubMed/NCBI
8	Gorvin CM, Newey PJ, Rogers A, Stokes V, Neville MJ, Lines KE, Ntali G, Lees P, Morrison PJ, Singhellakis PN, et al: Association of prolactin receptor (PRLR) variants with prolactinomas. Hum Mol Genet. 28:1023–1037. 2019. View Article : Google Scholar :
9	Kwinta BM, Grzywna E, Krzyżewski RM and Adamek D: The quantitative evaluation of the immunohistochemical expression of the pituitary adenomas. Folia Med Cracov. 57:83–96. 2017.
10	Naguy A: Pimozide: An old wine in a new bottle. Indian J Psychol Med. 39:382–383. 2017. View Article : Google Scholar : PubMed/NCBI
11	Preskorn SH: Changes in the product label for pimozide illustrate both the promises and the challenges of personalized medicine. J Clin Psychiatry. 73:1191–1193. 2012. View Article : Google Scholar : PubMed/NCBI
12	Friedman JI, Lindenmayer JP, Alcantara F, Bowler S, Parak M, White L, Iskander A, Parrella M, Adler DN, Tsopelas ND, et al: Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology. 36:1289–1295. 2011. View Article : Google Scholar : PubMed/NCBI
13	Rondanin R, Simoni D, Maccesi M, Romagnoli R, Grimaudo S, Pipitone RM, Meli M, Cascio A and Tolomeo M: Effects of pimo-zide derivatives on pSTAT5 in K562 cells. ChemMedChem. 12:1183–1190. 2017. View Article : Google Scholar : PubMed/NCBI
14	Rondanin R, Simoni D, Romagnoli R, Baruchello R, Marchetti P, Costantini C, Fochi S, Padroni G, Grimaudo S, Pipitone RM, et al: Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives. Bioorg Med Chem Lett. 24:4568–4574. 2014. View Article : Google Scholar : PubMed/NCBI
15	Li H, Zheng H, Sun Y, Yu Q and Li L: Signal transducer and activator of transcription 5a inhibited by pimozide may regulate survival of goat mammary gland epithelial cells by regulating parathyroid hormone-related protein. Gene. 551:279–289. 2014. View Article : Google Scholar : PubMed/NCBI
16	Chen JJ, Cai N, Chen GZ, Jia CC, Qiu DB, Du C, Liu W, Yang Y, Long ZJ and Zhang Q: The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma. Oncotarget. 8:17593–17609. 2017. View Article : Google Scholar :
17	Zhou W, Chen MK, Yu HT, Zhong ZH, Cai N, Chen GZ, Zhang P and Chen JJ: The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation. Int J Oncol. 48:322–328. 2016. View Article : Google Scholar
18	Hadzijusufovic E, Keller A, Berger D, Greiner G, Wingelhofer B, Witzeneder N, Ivanov D, Pecnard E, Nivarthi H, Schur F, et al: STAT5 is expressed in CD34⁺/CD38-stem cells and serves as a potential molecular target in ph-negative myeloproliferative neoplasms. Cancers (Basel). 12:10212020. View Article : Google Scholar
19	Subramaniam D, Angulo P, Ponnurangam S, Dandawate P, Ramamoorthy P, Srinivasan P, Iwakuma T, Weir SJ, Chastain K and Anant S: Suppressing STAT5 signaling affects osteosarcoma growth and stemness. Cell Death Dis. 11:1492020. View Article : Google Scholar : PubMed/NCBI
20	Zhao Y, Jin D, Lian W, Xing B, Feng M, Liu X and Wang R: Clinical characteristics and surgical outcome of prolactinoma in patients under 14 years old. Medicine (Baltimore). 98:e143802019. View Article : Google Scholar
21	Zhao Y, Xiao Z, Chen W, Yang J, Li T and Fan B: Disulfiram sensitizes pituitary adenoma cells to temozolomide by regulating O6-methylguanine-DNA methyltransferase expression. Mol Med Rep. 12:2313–2322. 2015. View Article : Google Scholar : PubMed/NCBI
22	Turhan AG: STAT5 as a CML target: STATinib therapies. Blood. 117:3252–3253. 2011. View Article : Google Scholar : PubMed/NCBI
23	Florio T: Adult pituitary stem cells: From pituitary plasticity to adenoma development. Neuroendocrinology. 94:265–277. 2011. View Article : Google Scholar : PubMed/NCBI
24	Pastrana E, Silva-Vargas V and Doetsch F: Eyes wide open: A critical review of sphere-formation as an assay for stem cells. Cell Stem Cell. 8:486–498. 2011. View Article : Google Scholar : PubMed/NCBI
25	Würth R, Barbieri F, Pattarozzi A, Gaudenzi G, Gatto F, Fiaschi P, Ravetti JL, Zona G, Daga A, Persani L, et al: Phenotypical and pharmacological characterization of stem-like cells in human pituitary adenomas. Mol Neurobiol. 54:4879–4895. 2017. View Article : Google Scholar
26	Santos-Pinheiro F, Penas-Prado M, Kamiya-Matsuoka C, Waguespack SG, Mahajan A, Brown PD, Shah KB, Fuller GN and McCutcheon IE: Treatment and long-term outcomes in pituitary carcinoma: A cohort study. Eur J Endocrinol. 181:397–407. 2019. View Article : Google Scholar : PubMed/NCBI
27	Akinduro OO, Lu VM, Izzo A, De Biase G, Vilanilam G, Van Gompel JJ, Bernet V, Donaldson A, Olomu O, Meyer FB, et al: Radiographic and hormonal regression in prolactinomas: An analysis of treatment failure. World Neurosurg. 129:e686–e694. 2019. View Article : Google Scholar : PubMed/NCBI
28	Huang HY, Lin SJ, Zhao WG and Wu ZB: Cabergoline versus bromocriptine for the treatment of giant prolactinomas: A quantitative and systematic review. Metab Brain Dis. 33:969–976. 2018. View Article : Google Scholar : PubMed/NCBI
29	Hachim IY, Shams A, Lebrun JJ and Ali S: A favorable role of prolactin in human breast cancer reveals novel pathway-based gene signatures indicative of tumor differentiation and favorable patient outcome. Hum Pathol. 53:142–152. 2016. View Article : Google Scholar : PubMed/NCBI
30	Wen Y, Zand B, Ozpolat B, Szczepanski MJ, Lu C, Yuca E, Carroll AR, Alpay N, Bartholomeusz C, Tekedereli I, et al: Antagonism of tumoral prolactin receptor promotes autophagy-related cell death. Cell Rep. 7:488–500. 2014. View Article : Google Scholar : PubMed/NCBI
31	Kalita A, Gupta S, Singh P, Surolia A and Banerjee K: IGF-1 stimulated upregulation of cyclin D1 is mediated via STAT5 signaling pathway in neuronal cells. IUBMB Life. 65:462–471. 2013. View Article : Google Scholar : PubMed/NCBI
32	Mao Y, Li Z, Lou C and Zhang Y: Expression of phosphorylated Stat5 predicts expression of cyclin D1 and correlates with poor prognosis of colonic adenocarcinoma. Int J Colorectal Dis. 26:29–35. 2011. View Article : Google Scholar
33	Brockman JL and Schuler LA: Prolactin signals via Stat5 and Oct-1 to the proximal cyclin D1 promoter. Mol Cell Endocrinol. 239:45–53. 2005. View Article : Google Scholar : PubMed/NCBI
34	Magné S, Caron S, Charon M, Rouyez MC and Dusanter-Fourt I: STAT5 and Oct-1 form a stable complex that modulates cyclin D1 expression. Mol Cell Biol. 23:8934–8945. 2003. View Article : Google Scholar : PubMed/NCBI
35	Qian YH, Xiao Q, Chen H and Xu J: Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway. Biochim Biophys Acta. 1793:764–771. 2009. View Article : Google Scholar : PubMed/NCBI
36	Fujinaka Y, Takane K, Yamashita H and Vasavada RC: Lactogens promote beta cell survival through JAK2/STAT5 activation and Bcl-XL upregulation. J Biol Chem. 282:30707–30717. 2007. View Article : Google Scholar : PubMed/NCBI
37	Kanie T, Abe A, Matsuda T, Kuno Y, Towatari M, Yamamoto T, Saito H, Emi N and Naoe T: TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways. Leukemia. 18:548–555. 2004. View Article : Google Scholar : PubMed/NCBI
38	Moldovan IM, Şuşman S, Pîrlog R, Jianu EM, Leucuţa DC, Melincovici CS, Crişan D and Florian IŞ: Molecular markers in the diagnosis of invasive pituitary adenomas-an immunohisto-chemistry study. Rom J Morphol Embryol. 58:1357–1364. 2017.
39	Bălinişteanu B, Cîmpean AM, Ceauşu AR, Corlan AS, Melnic E and Raica M: High Ki-67 expression is associated with prolactin secreting pituitary adenomas. Bosn J Basic Med Sci. 17:104–108. 2017.
40	Oshige T, Nakamura Y, Sasaki Y, Kawano S, Ohki T, Tsuruta M, Tokubuchi I, Nakayama H, Yamada K, Ashida K, et al: Bromocriptine as a potential glucose-lowering agent for the treatment of prolactinoma with type 2 diabetes. Intern Med. 58:3125–3128. 2019. View Article : Google Scholar : PubMed/NCBI
41	Gschwantler-Kaulich D, Grunt TW, Muhr D, Wagner R, Kölbl H and Singer CF: HER Specific TKIs exert their antineoplastic effects on breast cancer cell lines through the involvement of STAT5 and JNK. PLoS One. 11:e01463112016. View Article : Google Scholar : PubMed/NCBI
42	Hazzan T, Eberle J, Worm M and Babina M: Thymic stromal lymphopoietin interferes with the apoptosis of human skin mast cells by a dual strategy involving STAT5/Mcl-1 and JNK/Bcl-xL. Cells. 8:8292019. View Article : Google Scholar :
43	Kim U, Kim CY, Lee JM, Ryu B, Kim J, Shin C and Park JH: Pimozide inhibits the human prostate cancer cells through the generation of reactive oxygen species. Front Pharmacol. 10:15172020. View Article : Google Scholar : PubMed/NCBI
44	Nyga R, Pecquet C, Harir N, Gu H, Dhennin-Duthille I, Régnier A, Gouilleux-Gruart V, Lassoued K and Gouilleux F: Activated STAT5 proteins induce activation of the PI 3-kinase/Akt and Ras/MAPK pathways via the Gab2 scaffolding adapter. Biochem J. 390:359–366. 2005. View Article : Google Scholar : PubMed/NCBI
45	Gupta MA, Vujcic B, Pur DR and Gupta AK: Use of antipsychotic drugs in dermatology. Clin Dermatol. 36:765–773. 2018. View Article : Google Scholar : PubMed/NCBI
46	Biller BM: Hyperprolactinemia. Int J Fertil Womens Med. 44:74–77. 1999.PubMed/NCBI