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Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor

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Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Gastroenterology 2020;158:1433–1449 Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice Prasad Dandawate,1 Gaurav Kaushik,2 Chandrayee Ghosh,1 David Standing,1 Afreen Asif Ali Sayed,1 Sonali Choudhury,1 Dharmalingam Subramaniam,1 Ann Manzardo,3 Tuhina Banerjee,4 Santimukul Santra,4 Prabhu Ramamoorthy,1 Merlin Butler,3 Subhash B. Padhye,1,5 Joaquina Baranda,6 Anup Kasi,6 Weijing Sun,6 Ossama Tawfik,7 Domenico Coppola,8 Mokenge Malafa,8 Shahid Umar,2 Michael J. Soares,7,9,10,11 Subhrajit Saha,12 Scott J. Weir,1,13 Animesh Dhar,1 Roy A. Jensen,1,7 Sufi Mary Thomas,1,14 and Shrikant Anant1,2,5 1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas; 2Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas; 3Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, Kansas City, Kansas; 4Department of Chemistry, Pittsburg State University, Pittsburg, Kansas; 5Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune; 6Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas; 7Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas; 8Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; 9Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas; 10Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas; 11Center for Perinatal Research, Children’s Research Institute, Children’s Mercy–Kansas City, Kansas City, Missouri; 12Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas; 13Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; and 14Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas BASIC AND TRANSLATIONAL PANCREAS BACKGROUND & AIMS: Prolactin (PRL) signaling is up- compare levels of PRL and PRLR in multitumor tissue regulated in hormone-responsive cancers. The PRL receptor microarrays. We used structure-based virtual screening and (PRLR) is a class I cytokine receptor that signals via the Janus fragment-based drug discovery to identify compounds likely kinase (JAK)–signal transducer and activator of transcription to bind PRLR and interfere with its signaling. Human and mitogen-activated protein kinase pathways to regulate cell pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), proliferation, migration, stem cell features, and apoptosis. Pa- with or without knockdown of PRLR (clustered regularly tients with pancreatic ductal adenocarcinoma (PDAC) have high interspaced short palindromic repeats or small hairpin RNA), plasma levels of PRL. We investigated whether PRLR signaling were incubated with PRL or penfluridol and analyzed in contributes to the growth of pancreatic tumors in mice. proliferation and spheroid formation. C57BL/6 mice were METHODS: We used immunohistochemical analyses to given injections of UNKC-6141 cells, with or without Downloaded for Anonymous User (n/a) at University of Missouri Health Care from ClinicalKey.com by Elsevier on May 07, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 1434 Dandawate et al Gastroenterology Vol. 158, No. 5 knockdown of PRLR, into pancreas, and tumor development WHAT YOU NEED TO KNOW was monitored for 4 weeks, with some mice receiving pen- fluridol treatment for 21 days. Human pancreatic tumor tis- BACKGROUND AND CONTEXT sues were implanted into interscapular fat pads of NSG mice, fl Prolactin signaling is upregulated in hormone-responsive and mice were given injections of pen uridol daily for 28 cancers, and patients with pancreatic ductal days. Nude mice were given injections of Panc-1 cells, xeno- adenocarcinoma (PDAC) have high plasma levels of graft tumors were grown for 2 weeks, and mice were then prolactin. The prolactin receptor (PRLR) signals via the given intraperitoneal penfluridol for 35 days. Tumors were JAK–STAT and MAPK pathways to regulate cell collected from mice and analyzed by histology, immunohis- proliferation, migration, stem-cell features, and apoptosis. tochemistry, and immunoblots. RESULTS: Levels of PRLR NEW FINDINGS were increased in PDAC compared with nontumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated Levels of PRLR are increased in PDAC, and exposure of signaling via JAK2–signal transducer and activator of tran- pancreatic cancer cells to PRL increases their scription 3 and extracellular signal–regulated kinase, as well proliferation and migration. Antipsychotic drugs such as penfluridol block PRLR signaling in pancreatic cancer as formation of pancospheres and cell migration; these ac- cells and reduced their proliferation, induced autophagy, tivities were not observed in cells with PRLR knockdown. and slowed growth of xenograft tumors in mice. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several LIMITATIONS diphenylbutylpiperidine-class antipsychotic drugs as agents This study was performed in cell lines and mice. Studies in that decreased PRL-induced JAK2 signaling; incubation of humans are needed. pancreatic cancer cells with these compounds reduced their IMPACT proliferation and formation of panco spheres. Injections of 1 of these compounds, penfluridol, slowed the growth of Antipsychotic drugs such as penfluridol block JAK2 xenograft tumors in the different mouse models, reducing signaling in pancreatic cancer cells, slow tumor growth proliferation and inducing autophagy of the tumor cells. in mice, and might be tested in patients with PDAC. CONCLUSIONS: Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of cause of cancer-related deaths in the United States.11 Poor pancreatic cancer cells. Antipsychotic drugs, such as pen- prognosis, drug resistance, and high recurrence rates char- fluridol, block PRL signaling in pancreatic cancer cells to acterize PDAC after surgery.12 Here, we show that PRL in- reduce their proliferation, induce autophagy, and slow the duces both JAK2–STAT3 and extracellular signal–regulated growth of xenograft tumors in mice. These drugs might be kinase (ERK) signaling in the cells. PRLR knockdown tested in patients with PDAC. reduced the signaling and tumor growth in the orthotopic PDAC model, suggesting that PRLR may be an effective therapeutic target. To identify a small-molecule inhibitor, Keywords: Dopamine Receptor; Molecular Modeling; Combina- we developed an in silico model for the JAK2-interacting tion Therapy; Gemcitabine. domain and subsequently identified potential interacting diphenylbutylpiperidine (penfluridol, pimozide, fluspir- ilene) and phenothiazine (promethazine) antipsychotic TRANSLATIONAL PANCREAS rolactin (PRL) signaling has an established role in compounds. Using penfluridol as proof of principle, we maintaining pregnancy, mammary gland develop- show that it is effective in targeting PRLR signaling and BASIC AND P ment, immune regulation, adipocyte control, reproduction, suppressing tumor growth in the orthotopic PDAC model. and islet cell differentiation.1,2 Moreover, the pathway is Because penfluridol was initially identified as a dopamine implicated in multiple endocrine-driven tumors.3 More receptor D2 (DRD2) antagonist, we also determined recently, the pathway has been observed to play a role in whether its effect also occurs through DRD2. Although other tumor types, including colon and hepatocellular can- DRD2 expression is also induced in PDAC, the penfluridol cers.4,5 PRL receptor (PRLR) belongs to the class I cytokine effect on PDAC cells was not affected by DRD2 knockdown. fl receptor superfamily and lacks intrinsic kinase activity, This suggests that the pen uridol effect occurs through transducing signals including Janus kinase (JAK)–signal suppression of PRLR signaling. transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways through 6 Abbreviations used in this paper: AKT, protein kinase B; CRISPR, clus- kinases that interact with its cytoplasmic tail. The pathway tered regularly interspaced short palindromic repeats; DMEM, Dulbecco’s is implicated in the promotion of cell proliferation, migra- modified Eagle medium; DRD2, dopamine receptor D2; ERK, extracellular tion, stemness, and inhibition of apoptosis,7 as well as signal–regulated kinase; FBS, fetal bovine serum; JAK, Janus kinase; 8,9 MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; PDAC, chemoresistance. In colon cancers, PRL induces JAK2– pancreatic ductal adenocarcinoma; PDX, patient-derived xenograft; PRL, STAT3 signaling to affect stemness by up-regulating the prolactin; PRLR, prolactin receptor; shRNA, short hairpin RNA; SPR, sur- 5 face plasmon resonance; STAT, signal transducer and activator of tran- Notch pathway. scription; TCGA, The Cancer Genome Atlas; TMA, tumor microarray. We now show that PRLR-based signaling is active in Most current article pancreatic ductal adenocarcinoma (PDAC). The reason for fi © 2020 by the AGA Institute choosing PDAC is 2-fold: rst, patients with PDAC have high 0016-5085/$36.00 10 plasma levels of PRL ; second, PDAC remains a leading https://doi.org/10.1053/j.gastro.2019.11.279 Downloaded
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