Department of Neurology, University of California Irvine, Irvine, CA, USA.
Department of Pathology & Laboratory Medicine, University of California Irvine, Irvine, CA, USA.
J Neurooncol. 2019 Jan;141(2):267-276. doi: 10.1007/s11060-018-03040-8. Epub 2018 Nov 9.
Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas.
We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells.
Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator.
This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas.
Magmas（与粒细胞-巨噬细胞集落刺激因子信号转导有关的线粒体相关蛋白）是一种核基因，编码线粒体输入内膜转位酶亚基 Tim16。Magmas 高度保守，在哺乳动物细胞中广泛表达，对细胞活力至关重要。Magmas 的表达水平在前列腺癌和垂体腺瘤中增加。此外，通过 RNAi 沉默 Magmas 可使垂体腺瘤细胞对促凋亡刺激敏感，并诱导 G0/G1 积累。本研究旨在探讨小分子抑制剂抑制 Magmas 是否有益于恶性神经胶质瘤的治疗。
我们评估了 Magmas 在患者来源的胶质母细胞瘤组织样本和异种移植模型中的表达。我们研究了小分子 Magmas 抑制剂（BT#9）作为稳定的人类神经胶质瘤细胞系和高级别患者来源的神经胶质瘤干细胞样细胞治疗剂的可行性。
Magmas 在来自胶质瘤患者和异种移植的组织切片中过表达。体内研究表明，BT#9 可以在动物模型中穿过血脑屏障。BT#9 在神经胶质瘤细胞系中抑制 Magmas 显著降低细胞增殖，诱导凋亡并伴有空泡形成，并阻断迁移和侵袭。此外，BT#9 处理降低了神经胶质瘤细胞的呼吸功能，支持 Magmas 作为活性氧调节剂的作用。
这是 Magmas 在神经胶质瘤中作用的首次研究。我们的研究结果表明，Magmas 在神经胶质瘤细胞存活中起关键作用，通过小分子抑制剂靶向 Magmas 可能是神经胶质瘤的一种治疗策略。
