STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy
STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy
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DOI：
10.3390/ijms21031106
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Nawroth, Roman
中科院分区：
文献类型：
--
作者：
Hindupur, Sruthi, V;Schmid, Sebastian C.;Nawroth, Roman
JAK-STAT信号通路调控细胞分裂、细胞死亡和免疫调节等细胞过程。在实体瘤中已经发现了调节失调，STAT3的激活是预后不良的标志。本研究的目的是通过针对膀胱癌(BC)的这一通路来探索潜在的治疗策略。免疫组织化学方法检测149例浸润性膀胱癌组织中STAT3的高表达占51.3%。在10个细胞系中证实了JAK、STAT及其下游靶蛋白的表达。通过细胞存活率、免疫印迹、细胞凋亡率和细胞周期进程等方法分析JAK抑制剂ruxolitinib和BSK-805以及STAT3/5抑制剂Stattic、Nifuroxazide和SH-4-54对细胞生长的影响。用STAT3/5而不是JAK1/2抑制剂治疗可降低存活率、磷酸化STAT3和Cyclin-D1水平并增加细胞凋亡率。使用鸡绒毛膜尿囊膜(CAM)模型的肿瘤移植瘤对他汀类药物单一治疗有反应。他汀类药物与顺铂、多西他赛、吉西他滨、紫杉醇、CDK4/6抑制剂联用时表现为相加作用。他汀类药物与溶瘤腺病毒XVir-N-31联合使用可增加病毒复制和细胞裂解。我们的研究结果表明，STAT3/5抑制剂有望成为治疗膀胱癌的新型单一或联合治疗药物。
The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Statticwith the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.