Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice

摘要: Background & Aims Prolactin (PRL) signaling is up-regulated in hormone-responsive cancers. The PRL receptor (PRLR) a class I cytokine that signals via the Janus kinase (JAK)–signal transducer and activator of transcription mitogen-activated protein pathways to regulate cell proliferation, migration, stem features, apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels PRL. We investigated whether PRLR contributes growth tumors mice. Methods used immunohistochemical analyses compare multitumor tissue microarrays. structure-based virtual screening fragment-based drug discovery identify compounds likely bind interfere its signaling. Human lines (AsPC-1, BxPC-3, Panc-1, MiaPaCa-2), or without knockdown (clustered regularly interspaced short palindromic repeats small hairpin RNA), were incubated penfluridol analyzed proliferation spheroid formation. C57BL/6 mice given injections UNKC-6141 cells, PRLR, into pancreas, tumor development was monitored for 4 weeks, some receiving treatment 21 days. tissues implanted interscapular fat pads NSG mice, daily 28 Nude Panc-1 xenograft grown 2 then intraperitoneal 35 Tumors collected from by histology, immunohistochemistry, immunoblots. Results Levels increased PDAC compared nontumor tissues. Incubation activated JAK2–signal 3 extracellular signal–regulated kinase, as well formation pancospheres migration; these activities not observed cells knockdown. Pancreatic cancer formed significantly smaller identified several diphenylbutylpiperidine-class antipsychotic drugs agents decreased PRL-induced JAK2 signaling; incubation reduced their panco spheres. Injections 1 compounds, penfluridol, slowed different mouse models, reducing inducing autophagy cells. Conclusions are PDAC, exposure increases migration Antipsychotic drugs, such block reduce induce autophagy, slow These might be tested patients PDAC.