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首页> 外文期刊>Cellular Physiology and Biochemistry >Inhibition of Na-K ~+-2Cl ~- cotransporter isoform 1 accelerates temozolomidemediated apoptosis in glioblastoma cancer cells
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Inhibition of Na-K ~+-2Cl ~- cotransporter isoform 1 accelerates temozolomidemediated apoptosis in glioblastoma cancer cells

机译：抑制Na-K〜+ -2Cl〜-共转运蛋白亚型1促进成胶细胞介导的胶质母细胞瘤癌细胞凋亡

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摘要

The hallmark of apoptosis is a significant reduction in cell volume (AVD) resulting from loss of K ~+ iand Cl ~- _i. Loss of cell volume and lowering of ionic strength of intracellular K ~+ and Cl ~-occur before any other detectable characteristics of apoptosis. In the present study, temozolomide (TMZ) triggered loss of K ~+ iand Cl ~- _iand AVD in primary glioblastoma multiforme (GBM) cancer cells (GC) and GC cancer stem cells (GSC). We hypothesize that Na ~+-K ~+-2Cl ~-cotransporter isoform 1 (NKCC1) counteracts AVD during apoptosis in GBM cancer cells by regulating cell volume and Cl ~-homeostasis. NKCC1 protein was expressed in both GC and GSC and played an essential role in regulatory volume increase (RVI) in response to hypertonic cell shrinkage and isotonic cell shrinkage. Blocking NKCC1 activity with its potent inhibitor bumetanide abolished RVI. These cells maintained a basal [Cl ~-] _i(～ 68 mM) above the electrochemical equilibrium for Cl ~- _i. NKCC1 also functioned to replenish Cl ~- _ilevels following the loss of Cl ~- _i. TMZ-treated cells exhibited increased phosphorylation of NKCC1 and its up-stream novel Cl ~-/volume-sensitive regulatory kinase WNK1. Inhibition of NKCC1 activity with bumetanide accelerated AVD, early apoptosis, as well as activation of caspase-3 and caspase-8. Taken together, this study strongly suggests that NKCC1 is an essential mechanism in GBM cells to maintain K ~+, Cl ~-, and volume homeostasis to counteract TMZ-induced loss of K ~+, Cl ~- and AVD. Therefore, blocking NKCC1 function augments TMZ-induced apoptosis in glioma cells.
机译：凋亡的标志是由于K〜+ i和Cl〜-i的损失而导致细胞体积（AVD）的显着减少。在细胞凋亡的任何其他可检测特征之前，发生细胞体积的损失和细胞内K〜+和Cl〜的离子强度的降低。在本研究中，替莫唑胺（TMZ）触发了原发性胶质母细胞瘤（GBM）癌细胞（GC）和GC癌症干细胞（GSC）中K +和Cl-AVD的损失。我们假设Na〜+ -K〜+ -2Cl〜-共转运蛋白亚型1（NKCC1）通过调节细胞体积和Cl〜-稳态来抵消GBM癌细胞凋亡期间的AVD。 NKCC1蛋白在GC和GSC中均表达，并且在高渗细胞收缩和等渗细胞收缩中，在调节体积增加（RVI）中起重要作用。用其强效抑制剂布美他尼阻断NKCC1活性消除了RVI。这些电池维持高于Cl〜-_i的电化学平衡的基础[Cl〜-] _i（〜68 mM）。在丢失C1〜_i之后，NKCC1还起到补充C1〜_i水平的作用。经TMZ处理的细胞显示出NKCC1及其上游新型Cl-//体积敏感调节激酶WNK1的磷酸化增加。布美他尼抑制NKCC1活性可加速AVD，早期凋亡以及激活caspase-3和caspase-8。两者合计，这项研究强烈表明，NKCC1是GBM细胞维持K〜+，Cl〜-和体积稳态以抵消TMZ诱导的K〜+，Cl〜-和AVD丧失的基本机制。因此，阻断NKCC1功能可增加TMZ诱导的神经胶质瘤细胞凋亡。

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