The α1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers
The α1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers
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DOI：
10.1002/path.2172
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发表时间：
2007-06-01
影响因子：
7.3
通讯作者：
Kiss, R.
中科院分区：
文献类型：
--
作者：
Mijatovic, T.;Roland, I.;Kiss, R.
由于非小细胞肺癌（NSCLC）的总体5年存活率低至15%，即使在手术干预和在辅助化疗中使用更新的分子的情况下，也迫切需要新的生物靶标和相关的新型抗癌剂。本研究旨在评估Na+/K+-ATP酶α 1亚基作为NSCLC新靶点的潜力，并揭示α 1表达在相当大比例的NSCLC临床样本中显著高于正常肺组织。此外，通过抗α 1 siRNA降低A549 NSCLC细胞中的α 1表达导致这些癌细胞的增殖和迁移显著受损。最后，在研究的三种Cardenolides中，UNBS 1450已知与Na+/K+-ATP酶结合，并在人NSCLC的实验模型中显示出有效的体内抗肿瘤活性，是Na+/K+-ATP酶同工酶（α 1 β 1、α 2 β 1和α 3 β 1）最有效的抑制剂，最显著的是α 1 β 1。这反映在该化合物在所有评估的NSCLC细胞系中具有更有效的抗增殖活性（A549、Cal-12 T、NCI-H727和A427）; A549 NSCLC细胞增殖和迁移的显著损害，以及抗α 1 ARNA或UNBS 1450治疗后产生的相似形态，与异常胞质分裂的特征相关，在UNBS 1450的情况下，通过肌动蛋白细胞骨架的解体介导。总的来说，这些数据强烈表明，使用特定的强心内酯靶向Na+/K+-ATP酶油可以代表对抗某些NSCLC的新方法。版权所有（c）2007大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
With an overall 5 year survival rate as low as 15% for non-small cell lung cancer (NSCLC), even with surgical intervention and the use of newer molecules in adjuvant chemotherapy, there is an urgent need for new biological targets and associated novel anti-cancer agents. The present study was undertaken to evaluate the potential of the Na+/K+-ATPase al subunit as a novel target in NSCLC and revealed that al expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in al expression in A549 NSCLC cells by anti-alpha 1 siRNA resulted in markedly impaired proliferation and migration of these cancer cells. Finally, of three cardenolides investigated, UNBS1450, which is known to bind to Na+/K+-ATPase and displays potent anti-tumour activity in vivo in experimental models of human NSCLCs, is the most potent inhibitor of Na+/K+-ATPase isozymes (alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1), most strikingly of alpha 1 beta 1. This was reflected in the compound's more potent anti-proliferative activity in all NSCLC cell lines evaluated (A549, Cal-12T, NCI-H727 and A427); the first three of which over-express al. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha 1 ARNA or UNBS1450 treatment, was associated with features of abnormal cytokinesis, mediated in the case of UNBS1450 by disorganization of the actin cytoskeleton. Collectively these data strongly suggest that targeting the Na+/K+-ATPase oil using specific cardenolides could represent a novel means to combat certain NSCLCs. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.