Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice
Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice
复制标题
DOI：
10.1053/j.gastro.2019.11.279
复制
发表时间：
2020-04-01
期刊：
影响因子：
29.4
通讯作者：
Anant, Shrikant
中科院分区：
文献类型：
--
作者：
Dandawate, Prasad;Kaushik, Gaurav;Anant, Shrikant
背景与目的：催乳素（PRL）信号传导在乳腺癌反应性肿瘤中上调。PRL受体（PRLR）是I类细胞因子受体，其通过Janus激酶（JAK）-信号转导子和转录激活子以及促分裂原活化蛋白激酶途径发出信号以调节细胞增殖、迁移、干细胞特征和凋亡。胰腺导管腺癌（PDAC）患者血浆PRL水平较高。我们调查是否PRLR信号有助于胰腺tumors in mice.METHODS的生长：我们使用免疫组化分析比较多肿瘤组织微阵列中的PRL和PRLR水平。我们使用基于结构的虚拟筛选和基于片段的药物发现来鉴定可能结合PRLR并干扰其信号传导的化合物。将人胰腺细胞系（AsPC-1、BxPC-3、Panc-1和MiaPaCa-2）与PRL或五氟利多一起孵育，并分析其增殖和球状体形成，其中PRLR（成簇的规则间隔短回文重复序列或小发夹RNA）敲减或未敲减。将UNKC-6141细胞注射到C57 BL/6小鼠的胰腺中，有或没有PRLR敲低，并监测肿瘤发展4周，其中一些小鼠接受五氟利多治疗21天。将人胰腺肿瘤组织植入NSG小鼠的肩胛间脂肪垫中，每天给小鼠注射五氟利多，持续28天。给裸鼠注射Panc-1细胞，异种移植肿瘤生长2周，然后给小鼠腹膜内注射五氟利多35天。收集小鼠肿瘤，并通过组织学，免疫组织化学和免疫印迹分析。结果：与非肿瘤胰腺组织相比，PDAC中PRLR的水平增加。与PRL孵育的胰腺细胞系通过JAK 2-信号转导子和转录激活子3和细胞外信号调节激酶激活信号传导，以及形成pancosphere和细胞迁移;在PRLR敲低的细胞中未观察到这些活性。PRLR敲低的胰腺癌细胞在小鼠中形成了明显更小的肿瘤。我们确定了几种二苯基丁基哌啶类抗精神病药物作为降低PRL诱导的JAK 2信号传导的药物;胰腺癌细胞与这些化合物的孵育减少了它们的增殖和panco球体的形成。注射1这些化合物，五氟利多，减缓了异种移植肿瘤在不同的小鼠模型的生长，减少增殖和诱导自噬的肿瘤cells.CONCLUSIONS：水平的催乳素受体增加PDAC，暴露于PRL增加胰腺癌细胞的增殖和迁移。五氟利多等抗精神病药物可以阻断胰腺癌细胞中的PRL信号传导，以减少其增殖、诱导自噬并减缓小鼠异种移植肿瘤的生长。这些药物可以在PDAC患者中进行测试。
BACKGROUND & AIMS: Prolactin (PRL) signaling is upregulated in hormone-responsive cancers. The PRL receptor (PRLR) is a class I cytokine receptor that signals via the Janus kinase (JAK)-signal transducer and activator of transcription and mitogen-activated protein kinase pathways to regulate cell proliferation, migration, stem cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to the growth of pancreatic tumors in mice.METHODS: We used immunohistochemical analyses to compare levels of PRL and PRLR in multitumor tissue microarrays. We used structure-based virtual screening and fragment-based drug discovery to identify compounds likely to bind PRLR and interfere with its signaling. Human pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), with or without knockdown of PRLR (clustered regularly interspaced short palindromic repeats or small hairpin RNA), were incubated with PRL or penfluridol and analyzed in proliferation and spheroid formation. C57BL/6 mice were given injections of UNKC-6141 cells, with or without knockdown of PRLR, into pancreas, and tumor development was monitored for 4 weeks, with some mice receiving penfluridol treatment for 21 days. Human pancreatic tumor tissues were implanted into interscapular fat pads of NSG mice, and mice were given injections of penfluridol daily for 28 days. Nude mice were given injections of Panc-1 cells, xenograft tumors were grown for 2 weeks, and mice were then given intraperitoneal penfluridol for 35 days. Tumors were collected from mice and analyzed by histology, immunohistochemistry, and immunoblots.RESULTS: Levels of PRLR were increased in PDAC compared with nontumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated signaling via JAK2-signal transducer and activator of transcription 3 and extracellular signal-regulated kinase, as well as formation of pancospheres and cell migration; these activities were not observed in cells with PRLR knockdown. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several diphenylbutylpiperidine-class antipsychotic drugs as agents that decreased PRL-induced JAK2 signaling; incubation of pancreatic cancer cells with these compounds reduced their proliferation and formation of panco spheres. Injections of 1 of these compounds, penfluridol, slowed the growth of xenograft tumors in the different mouse models, reducing proliferation and inducing autophagy of the tumor cells.CONCLUSIONS: Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of pancreatic cancer cells. Antipsychotic drugs, such as penfluridol, block PRL signaling in pancreatic cancer cells to reduce their proliferation, induce autophagy, and slow the growth of xenograft tumors in mice. These drugs might be tested in patients with PDAC.