Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling
Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling
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DOI：
10.1158/0008-5472.can-10-1253
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发表时间：
2010-10-01
期刊：
影响因子：
11.2
通讯作者：
Poet, Mallorie
中科院分区：
文献类型：
--
作者：
Milosavljevic, Nina;Duranton, Christophe;Poet, Mallorie
顺铂是一种抗肿瘤药物，主要通过DNA加合物的形成导致细胞死亡。在患者中，它表现出一系列不太可能与其基因组作用相关的短期副作用。由于顺铂已被证明可以改变不同细胞系统的膜特性，我们研究了其对机械敏感离子转运体和通道的影响。我们在这里表明，顺铂是机械敏感性Na+/ H+交换剂NHE-1的非竞争性抑制剂，半抑制浓度为30 μ g/mL，与V-max和Hill系数的降低有关。我们还发现它以相似的浓度阻断Cl-和K+机械敏感通道VSORC和TREK-1。相比之下，非机械敏感性的Cl-和K+通道CFTR和TASK-1以及Na+偶联的葡萄糖转运通道分别与VSORC、TREK-1和NHE-1具有相同的功能特征，对顺铂不敏感。接下来，我们研究了顺铂的作用是否由于直接作用于膜或皮质肌动蛋白重塑而影响机械传感器。使用扫描电镜、体内肌动蛋白标记和原子力显微镜，我们没有观察到60和120 μ g/mL顺铂对杨氏模量和肌动蛋白细胞骨架的任何修饰，而这些浓度改变了膜形态。我们的研究结果揭示了顺铂的新机制，它影响参与细胞命运程序和/或在机械敏感器官中表达的机械敏感通道和转运蛋白，其中顺铂引起强烈的继发性效应，如内耳或周围神经系统。这些结果可能构成了该药物先前不相关效应的共同分母。癌症Res;70 (19);7514 - 22所示。(c) 2010年aacr。
Cisplatin is an antineoplastic drug, mostly documented to cause cell death through the formation of DNA adducts. In patients, it exhibits a range of short-term side effects that are unlikely to be related to its genomic action. As cisplatin has been shown to modify membrane properties in different cell systems, we investigated its effects on mechanosensitive ion transporters and channels. We show here that cisplatin is a noncompetitive inhibitor of the mechanosensitive Na+/ H+ exchanger NHE-1, with a half-inhibition concentration of 30 mu g/mL associated with a decrease in V-max and Hill coefficient. We also showed that it blocks the Cl- and K+ mechanosensitive channels VSORC and TREK-1 at similar concentrations. In contrast, the nonmechanosensitive Cl- and K+ channels CFTR and TASK-1 and the Na+-coupled glucose transport, which share functional features with VSORC, TREK-1, and NHE-1, respectively, were insensitive to cisplatin. We next investigated whether cisplatin action was due to a direct effect on membrane or to cortical actin remodeling that would affect mechanosensors. Using scanning electron microscopy, in vivo actin labeling, and atomic force microscopy, we did not observe any modification of the Young's modulus and actin cytoskeleton for up to 60 and 120 mu g/mL cisplatin, whereas these concentrations modified membrane morphology. Our results reveal a novel mechanism for cisplatin, which affects mechanosensitive channels and transporters involved in cell fate programs and/or expressed in mechanosensitive organs in which cisplatin elicits strong secondary effects, such as the inner ear or the peripheral nervous system. These results might constitute a common denominator to previously unrelated effects of this drug. Cancer Res; 70(19); 7514-22. (C) 2010 AACR.