Wan Yu-Ying, Zhang Jian-Feng, Yang Zhang-Jian, Jiang Li-Ping, Wei Yong-Fang, Lai Qi-Nan, Wang Jian-Bin, Xin Hong-Bo, Han Xiao-Jian
Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, P.R. China.
Department of Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang, Jiangxi, P.R. China.
Oncol Rep. 2014 Aug;32(2):619-26. doi: 10.3892/or.2014.3235. Epub 2014 Jun 5.
Glioblastoma is one of the most aggressive brain tumors with high morbidity and mortality. Hypoxia is often the common characteristic of tumor microenvironment, and hypoxia-inducible factor-1α (HIF-1α) is an essential factor regulating the migratory activity of cancer cells including glioblastoma. Recently, mitochondrial dynamics was found to be involved in the aggression of cancer cells. However, whether dynamin-related protein 1 (Drp1) contributes to the migration of human glioblastoma cells under hypoxia remains unknown. In the present study, hypoxia was found to upregulate the transcription and expression of Drp1, and stimulated mitochondrial fission in glioblastoma U251 cells. Inhibition of HIF-1α with echinomycin blocked hypoxia‑induced expression of Drp1. Notably, Drp1 inhibitor Mdivi-1 efficiently attenuated hypoxia-induced mitochondrial fission and migration of U251 cells. In addition, three U251 stable cell lines expressing GFP, GFP-Drp1 and dominant negative GFP-Drp1‑K38A were established to examine the direct role of Drp1 in hypoxia-induced migration. MTT assay showed that there was no significant difference in proliferation of three cell lines. Compared with the GFP cell line, exogenously expressed GFP-Drp1-K38A inhibited hypoxia-induced migration of U251 cells, while stable expression of GFP-Drp1 enhanced the migration of U251 cells under hypoxia. Therefore, this study indicates the involvement of Drp1 in hypoxia-induced migration of human glioblastoma U251 cells, and suggests Drp1 to be a potential therapeutic target to suppress the aggression of glioblastoma in the future.
胶质母细胞瘤是最具侵袭性的脑肿瘤之一，发病率和死亡率都很高。缺氧通常是肿瘤微环境的共同特征，缺氧诱导因子-1α（HIF-1α）是调节包括胶质母细胞瘤在内的癌细胞迁移活性的关键因子。最近，线粒体动力学被发现与癌细胞的侵袭有关。然而，动力蛋白相关蛋白1（Drp1）是否在缺氧条件下促进人胶质母细胞瘤细胞的迁移仍不清楚。在本研究中，发现缺氧可上调Drp1的转录和表达，并刺激胶质母细胞瘤U251细胞中的线粒体分裂。用棘霉素抑制HIF-1α可阻断缺氧诱导的Drp1表达。值得注意的是，Drp1抑制剂Mdivi-1有效减弱了缺氧诱导的U251细胞线粒体分裂和迁移。此外，建立了三种表达绿色荧光蛋白（GFP）、GFP-Drp1和显性负性GFP-Drp1-K38A的U251稳定细胞系，以研究Drp1在缺氧诱导迁移中的直接作用。MTT法检测显示三种细胞系的增殖无显著差异。与GFP细胞系相比，外源性表达GFP-Drp1-K38A抑制了缺氧诱导的U251细胞迁移，而GFP-Drp1的稳定表达增强了U251细胞在缺氧条件下的迁移。因此，本研究表明Drp1参与了缺氧诱导的人胶质母细胞瘤U251细胞迁移，并提示Drp1可能是未来抑制胶质母细胞瘤侵袭的潜在治疗靶点。
