Lefranc Florence, Mijatovic Tatjana, Kondo Yasuko, Sauvage Sébastien, Roland Isabelle, Debeir Olivier, Krstic Danijela, Vasic Vesna, Gailly Philippe, Kondo Seiji, Blanco Gustavo, Kiss Robert
Department of Neurosurgery, Erasme Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium.
Neurosurgery. 2008 Jan;62(1):211-21; discussion 221-2. doi: 10.1227/01.NEU.0000311080.43024.0E.
Ion transporters play pivotal roles in cancer cell migration in general and in glioblastomas (GBMs) in particular. However, the specific role of Na/K-ATPase (the sodium pump) and, in particular, its alpha1 subunit, has remained unexplored in GBMs.
The expression of Na+/K+ -ATPase alpha1 in GBM clinical samples, normal brain tissue, and a human GBM cell line has been investigated. Using the novel cardenolide UNBS1450 (Unibioscreen, Brussels, Belgium), which is a ligand of the sodium pump, we have characterized the effects of inhibiting Na+/K+ -ATPase alpha1 in human GBM cells with respect to cell proliferation; morphology; impact on intracellular Na+, Ca2+, and adenosine triphosphate; and changes in the actin cytoskeleton. We have investigated the mechanism by which UNBS1450 overcomes the apoptosis resistance of GBMs and determined its anti-tumor effects in comparative studies in vitro in GBM cell viability assays and in vivo using an orthotopic human GBM xenograft model.
Overall, the alpha1 subunit of Na+/K+ -ATPase is highly expressed in a majority of glioblastomas compared with normal brain tissues, and by binding to this subunit in human U373-MG GBM cells, UNBS1450 impairs cell proliferation and migration via an intracellular adenosine triphosphate decrease-mediated disorganization of the actin cytoskeleton and cytotoxic proautophagic effects. UNBS1450 also significantly increases the in vivo survival of mice orthotopically grafted with U373-MG GBM cells.
Inhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.
离子转运体在癌细胞迁移中普遍发挥关键作用，在胶质母细胞瘤（GBM）中尤为如此。然而，钠钾ATP酶（钠泵），尤其是其α1亚基在GBM中的具体作用仍未得到探索。
研究了钠钾ATP酶α1在GBM临床样本、正常脑组织和人GBM细胞系中的表达。使用新型强心甾醇UNBS1450（比利时布鲁塞尔的Unibioscreen公司），它是钠泵的一种配体，我们已表征了抑制人GBM细胞中钠钾ATP酶α1对细胞增殖、形态、对细胞内钠离子、钙离子和三磷酸腺苷的影响以及肌动蛋白细胞骨架变化的作用。我们研究了UNBS1450克服GBM凋亡抗性的机制，并在体外GBM细胞活力测定的比较研究中以及使用原位人GBM异种移植模型在体内确定了其抗肿瘤作用。
总体而言，与正常脑组织相比，钠钾ATP酶的α1亚基在大多数胶质母细胞瘤中高表达，并且通过在人U373 - MG GBM细胞中与该亚基结合，UNBS1450通过细胞内三磷酸腺苷减少介导的肌动蛋白细胞骨架紊乱和细胞毒性自噬作用损害细胞增殖和迁移。UNBS1450还显著提高了原位移植U373 - MG GBM细胞的小鼠的体内存活率。
抑制人GBM细胞中的钠钾ATP酶α1亚基会损害细胞迁移和细胞增殖。
