Imatinib inhibits the malignancy of hepatocellular carcinoma by suppressing autophagy
Imatinib inhibits the malignancy of hepatocellular carcinoma by suppressing autophagy
复制标题
伊马替尼通过抑制自噬抑制肝细胞癌恶性肿瘤
DOI：
10.1016/j.ejphar.2021.174217
复制
发表时间：
2021
影响因子：
5
通讯作者：
Xie Wei-Fen
中科院分区：
文献类型：
--
作者：
Xiao Meng-Chao;Qian Hui;Huang Chen-Kai;Zheng Bai-Nan;Yan Fang-Zhi;Liu Fang;Zhang Xin;Chen Shi-Jie;Luo Cheng;Xie Wei-Fen
肝细胞癌（HCC）是最常见的癌症之一，具有较高的发病率和死亡率。最近的研究表明，伊马替尼，一种选择性酪氨酸激酶抑制剂，抑制肝细胞癌的生长。然而，伊马替尼对HCC的作用及其机制仍在研究中。在这项研究中，我们证明了伊马替尼在体外抑制肝癌细胞的增殖，迁移和侵袭，并在体内对小鼠肝癌异种移植物产生抗肿瘤作用。伊马替尼治疗降低了HCC细胞和HCC异种移植物中AKT的磷酸化，并增加了p62（蛋白隔离体1）和LC 3（微管相关蛋白1A/1B-轻链3）的水平。扫描共聚焦显微镜分析与mRFP-GFP-LC 3报告和透射电子显微镜分析表明，伊马替尼抑制自噬通量通过阻碍形成的自溶体。此外，伊马替尼逆转了索拉非尼诱导的自噬，与单药治疗相比，伊马替尼和索拉非尼联合治疗在HCC细胞中发挥了协同作用。我们的集体数据表明，伊马替尼可能通过作为酪氨酸激酶和自噬的抑制剂靶向HCC;在这里，我们建议伊马替尼可能是临床上有前途的HCC治疗药物。
Hepatocellular carcinoma (HCC) is one of the most common cancers and is associated with high morbidity and mortality rates. Recent research indicated that imatinib, a selective tyrosine kinase inhibitor, suppressed the growth of hepatocellular carcinoma. However, the effect of imatinib on HCC and its mechanism remain under investigated. In this study, we demonstrated that imatinib inhibited the proliferation, migration and invasion of HCC cells in vitro and exerted antitumour effects on HCC xenografts in mice in vivo. Imatinib treatment decreased the phosphorylation of AKT and increased the levels of both p62 (protein sequestosome 1) and LC3 (microtubule-associated protein 1A/1B-light chain 3) in HCC cells and HCC xenografts. Scanning confocal microscopy analysis with a mRFP-GFP-LC3 reporter and transmission electron microscopy analysis revealed that imatinib suppressed the autophagic flux by obstructing the formation of autolysosomes. Moreover, imatinib reversed the autophagy induced by sorafenib, and combined treatment with imatinib and sorafenib exerted a synergetic effect in HCC cells compared with monotherapy. Our collective data suggested that imatinib may target HCC by acting as an inhibitor of both tyrosine kinase and autophagy; here, we propose that imatinib could be a promising therapeutic agent for HCC in the clinic.