JSI-124通过诱导自噬和凋亡在小鼠恶性间皮瘤中抑制细胞增殖和肿瘤生长。
JSI-124 inhibits cell proliferation and tumor growth by inducing autophagy and apoptosis in murine malignant mesothelioma.
发表日期：2023 Aug 29
作者：
Chengke Zhang, Qifeng Sun, Jiangfeng Zhao, Ning Jiang, Yingtao Hao, Junwen Luo, Saraf Karim, Licun Wu, Marc de Perrot, Chuanliang Peng, Xiaogang Zhao
来源：
Cell Death & Disease
摘要：
恶性胸膜间皮瘤（MPM）主要由石棉暴露引起，与其他癌症类型相比，其预后较差且缺乏有效治疗。细胞内转录因子信号转导与转录激活因子3（STAT3）在大多数人类癌症中过度表达和高度活化。本研究考察了STAT3在小鼠MPM中的作用。通过选择性抑制剂JSI-124抑制Janus激酶2（JAK2）/STAT3通路对小鼠MPM具有抗肿瘤效应。具体而言，我们证明了JSI-124抑制了小鼠MPM细胞的生长并诱导了凋亡和自噬细胞死亡。将RN5和AB12细胞暴露于JSI-124后，通过Bcl-2家族蛋白质引发了凋亡。JSI-124触发了自噬体的形成、积累以及LC3I到LC3II的转化。自噬抑制剂氯喹（CQ）和巴菲霉素A1（Baf-A1）抑制了自噬并增加了RN5和AB12细胞对JSI-124诱导的凋亡的敏感性。我们的数据表明，JSI-124是一种有希望的MPM治疗药物。© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.
Malignant pleural mesothelioma (MPM), mainly caused by asbestos exposure, has a poor prognosis and lacks effective treatment compared with other cancer types. The intracellular transcription factor signal transducer and activator of transcription 3 (STAT3) is overexpressed and hyperactivated in most human cancers. In this study, the role of STAT3 in murine MPM was examined. Inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway with the selective inhibitor JSI-124 has an antitumor effect in murine MPM. Specifically, we demonstrated that JSI-124 inhibits murine MPM cell growth and induces apoptotic and autophagic cell death. Exposure of RN5 and AB12 cells to JSI-124 resulted in apoptosis via the Bcl-2 family of proteins. JSI-124 triggered autophagosome formation, accumulation, and conversion of LC3I to LC3II. Autophagy inhibitors, Chloroquine (CQ) and Bafilomycin A1 (Baf-A1), inhibited autophagy and sensitized RN5 and AB12 cells to JSI-124-induced apoptosis. Our data indicate that JSI-124 is a promising therapeutic agent for MPM treatment.© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.