Li Shirong, Dai Zhi, Yang Dong, Li Wenxuan, Dai Hongjuan, Sun Bin, Liu Xiuyun, Xie Xin, Xu Rong, Zhao Xudong
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province Kunming 650223, Yunnan, China.
Kunming College of Life Science, University of Chinese Academy of Sciences Kunming 650204, Yunnan, China.
Am J Cancer Res. 2019 Jun 1;9(6):1293-1308. eCollection 2019.
Glioblastoma (GBM) is the most frequent brain cancer with poor prognosis and few therapies and urgently requires effective treatments. Na/K-ATPase is considered as a target for GBM therapy and development of anticancer drugs. Cardiac glycosides bind the Na/K-ATPase α subunit to inhibit enzymatic activity and are promising candidates for anticancer drug development including GBM. However, the comparatively higher doses required for effective anticancer actions cause severe cardiotoxicity. Selectively targeting the ATPase Na/K transporting subunit beta 2 (ATP1B2) that is not expressed in the heart might avoid the cardiotoxicity. However, the effect of targeting ATP1B2 in GBM remains unknown. In this study, we found that high ATP1B2 expression is significantly associated with poor prognosis of patients with GBM. ATP1B2 silencing in GBM cells resulted in remarkably cell cycle arrest at the G2/M phase and apoptosis with concomitant increase in intracellular Ca and activation of p38 kinase, similar to Na/K-ATPase inhibition by the classic cardiac glycoside digoxin. ATP1B2 is expressed higher in glioblastoma stem-like cells (GSCs) than in GBM cells and its downregulation induces apoptosis of GSCs. Furthermore, inducible ATP1B2 knockdown significantly inhibit tumor growth . Our data suggest ATP1B2 has potential as a therapeutic target for GBM.
胶质母细胞瘤（GBM）是最常见的脑癌，预后较差且治疗手段有限，迫切需要有效的治疗方法。钠钾ATP酶被认为是GBM治疗和抗癌药物开发的一个靶点。强心苷与钠钾ATP酶α亚基结合以抑制酶活性，是包括GBM在内的抗癌药物开发的有前景的候选药物。然而，有效抗癌作用所需的相对较高剂量会导致严重的心脏毒性。选择性靶向在心脏中不表达的ATP酶钠钾转运亚基β2（ATP1B2）可能会避免心脏毒性。然而，靶向ATP1B2在GBM中的作用仍不清楚。在本研究中，我们发现高ATP1B2表达与GBM患者的不良预后显著相关。GBM细胞中ATP1B2沉默导致细胞周期在G2/M期显著停滞和细胞凋亡，同时细胞内钙增加和p38激酶激活，这与经典强心苷地高辛抑制钠钾ATP酶相似。ATP1B2在胶质母细胞瘤干细胞样细胞（GSCs）中的表达高于GBM细胞，其下调诱导GSCs凋亡。此外，诱导性ATP1B2敲低显著抑制肿瘤生长。我们的数据表明ATP1B2有潜力成为GBM的治疗靶点。
