Department of Thoracic Surgery, Army General Hospital of PLA, Beijing 100700, P.R. China.
Int J Oncol. 2018 Dec;53(6):2409-2422. doi: 10.3892/ijo.2018.4586. Epub 2018 Oct 8.
Mammalian STE20-like kinase 1 (Mst1) is well recognized as a major tumor suppressor in cancer development, growth, metabolic reprogramming, metastasis, cell death and recurrence. However, the roles of Mst1 in non-small cell lung cancer (NSCLC) A549 cell phenotypic alterations remain to be elucidated. The present study aimed to explore the functional role and underlying mechanisms of Mst1 with regards to A549 cell proliferation, migration and apoptosis; this study focused on mitochondrial homeostasis and Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/F‑actin pathways. The results demonstrated that Mst1 was downregulated in A549 cells compared with in a normal pulmonary epithelial cell line. Subsequently, overexpression of Mst1 in A549 cells reduced cell viability and promoted cell apoptosis. Furthermore, overexpression of Mst1 suppressed A549 cell proliferation and migration. At the molecular level, the reintroduction of Mst1 in A549 cells led to activation of mitochondrial apoptosis, as evidenced by a reduction in mitochondrial potential, overproduction of ROS, cytochrome c release from the mitochondria into the nucleus, and upregulation of pro-apoptotic protein expression. In addition, Mst1 overexpression was closely associated with impaired mitochondrial respiratory function and suppressed cellular energy metabolism. Functional studies illustrated that Mst1 overexpression activated ROCK1/F-actin pathways, which highly regulate mitochondrial function. Inhibition of ROCK1/F-actin pathways in A549 cells sustained mitochondrial homeostasis, alleviated caspase-9-dependent mitochondrial apoptosis, enhanced cancer cell migration and increased cell proliferation. In conclusion, these data firmly established the regulatory role of Mst1 in NSCLC A549 cell survival via the modulation of ROCK1/F-actin pathways, which may provide opportunities for novel treatment modalities in clinical practice.
哺乳动物 STE20 样激酶 1（Mst1）被公认为癌症发展、生长、代谢重编程、转移、细胞死亡和复发的主要肿瘤抑制因子。然而，Mst1 在非小细胞肺癌（NSCLC）A549 细胞表型改变中的作用仍有待阐明。本研究旨在探讨 Mst1 对 A549 细胞增殖、迁移和凋亡的功能作用及潜在机制；本研究重点关注线粒体稳态和 Rho 相关卷曲螺旋蛋白激酶 1（ROCK1）/F-肌动蛋白通路。结果表明，与正常肺上皮细胞系相比，A549 细胞中 Mst1 表达下调。随后，在 A549 细胞中过表达 Mst1 可降低细胞活力并促进细胞凋亡。此外，过表达 Mst1 可抑制 A549 细胞的增殖和迁移。在分子水平上，将 Mst1 重新引入 A549 细胞后，线粒体凋亡被激活，表现为线粒体膜电位降低、ROS 产生增加、细胞色素 c 从线粒体释放到核内以及促凋亡蛋白表达上调。此外，Mst1 的过表达与受损的线粒体呼吸功能和抑制的细胞能量代谢密切相关。功能研究表明，Mst1 过表达激活了 ROCK1/F-actin 通路，该通路高度调节线粒体功能。在 A549 细胞中抑制 ROCK1/F-actin 通路可维持线粒体稳态，减轻 caspase-9 依赖性线粒体凋亡，增强癌细胞迁移并增加细胞增殖。综上所述，这些数据通过调节 ROCK1/F-actin 通路证实了 Mst1 在 NSCLC A549 细胞存活中的调节作用，这可能为临床实践中的新治疗方法提供机会。
