Chao Yuewen, Wang Yan, Liu Xuejiao, Ma Peng, Shi Yi, Gao Jian, Shi Qiong, Hu Jinxia, Yu Rutong, Zhou Xiuping
The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, China.
J Neurooncol. 2015 Jan;121(2):279-88. doi: 10.1007/s11060-014-1654-4. Epub 2014 Nov 6.
Mammalian sterile 20-like 1 (Mst1), an upstream serine/threonine-specific protein kinase of the Hippo pathway, is reported to play important roles in tumor suppression and organ size regulation in mammals via regulating cell proliferation and survival. However, whether it is involved in the pathogenesis of malignant gliomas remains poorly understood. Therefore, in the present work, we examined the effect and mechanism of Mst1 on the proliferation and apoptosis of malignant glioma cells. The cell proliferation and growth of glioma cells were examined by EdU incorporation and CCK-8 assay. In addition, the cell apoptosis was assessed by flow cytometry. We found that down-regulation of Mst1 promoted glioma cell proliferation and growth, but inhibited the cell apoptosis. Consistent with this, over-expression of Mst1 inhibited glioma cell proliferation and growth. Interestingly, Mst1 did not affect the phosphorylation of YAP1, the key downstream molecule of Hippo pathway. However, Mst1 was found to bind to AKT in glioma cell and negatively regulated AKT and mTOR activity. Finally, the increased cell proliferation rate induced by Mst1 down-regulation was partially abolished by down-regulation of AKT1. Meanwhile, glioma cell growth inhibition induced by Mst1 over-expression was partially rescued by over-expression of AKT1. Taken together, these findings suggest that Mst1 regulates proliferation of glioma cells via AKT/mTOR signaling pathway.
哺乳动物不育 20 样激酶 1（Mst1）是 Hippo 通路的上游丝氨酸/苏氨酸特异性蛋白激酶，据报道它通过调节细胞增殖和存活在哺乳动物的肿瘤抑制和器官大小调节中发挥重要作用。然而，它是否参与恶性胶质瘤的发病机制仍知之甚少。因此，在本研究中，我们研究了 Mst1 对恶性胶质瘤细胞增殖和凋亡的影响及机制。通过 EdU 掺入法和 CCK-8 测定法检测胶质瘤细胞的增殖和生长。此外，通过流式细胞术评估细胞凋亡。我们发现 Mst1 的下调促进了胶质瘤细胞的增殖和生长，但抑制了细胞凋亡。与此一致，Mst1 的过表达抑制了胶质瘤细胞的增殖和生长。有趣的是，Mst1 不影响 Hippo 通路关键下游分子 YAP1 的磷酸化。然而，发现 Mst1 在胶质瘤细胞中与 AKT 结合，并负向调节 AKT 和 mTOR 活性。最后，AKT1 的下调部分消除了 Mst1 下调诱导的细胞增殖率增加。同时，AKT1 的过表达部分挽救了 Mst1 过表达诱导的胶质瘤细胞生长抑制。综上所述，这些发现表明 Mst1 通过 AKT/mTOR信号通路调节胶质瘤细胞的增殖。
