The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers.
The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers.
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发表时间：
2007
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通讯作者：
T. Mijatovic;I. Roland;E. Van Quaquebeke;B. Nilsson;A. Mathieu;F. Van Vynckt;F. Darro;G. Blanco-G.-Blanc
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作者：
T. Mijatovic;I. Roland;E. Van Quaquebeke;B. Nilsson;A. Mathieu;F. Van Vynckt;F. Darro;G. Blanco-G.-Blanc
非小细胞肺癌（NSCLC）的总体5年生存率低至15%，即使在手术干预和使用新分子辅助化疗的情况下，迫切需要新的生物学靶点和相关的新型抗癌药物。本研究旨在评估Na(+)/K(+)- atp酶alpha1亚基作为非小细胞肺癌新靶标的潜力，结果显示，与正常肺组织相比，在相当比例的非小细胞肺癌临床样本中，alpha1的表达明显更高。此外，通过抗α 1 siRNA降低α 1在A549 NSCLC细胞中的表达，导致这些癌细胞的增殖和迁移明显受损。最后，在所研究的三种石斛内酯中，UNBS1450是Na(+)/K(+)- atp酶的最有效抑制剂（α 1beta1， α 2beta1和α 3beta1），最显著的是α 1beta1。UNBS1450已知与Na(+)/K(+)- atp酶结合，并在人非小细胞肺癌实验模型中显示出强大的抗肿瘤活性。这反映在该化合物在所有被评估的NSCLC细胞系（A549、Cal-12T、NCI-H727和A427）中具有更强的抗增殖活性；其中前三个过度表达了alpha1。抗α 1 siRNA或UNBS1450治疗后，A549 NSCLC细胞增殖和迁移的显著损伤，以及导致的相似形态，与异常细胞分裂的特征有关，在UNBS1450的情况下，异常细胞分裂是由肌动蛋白细胞骨架的破坏介导的。总的来说，这些数据强烈表明，使用特定的心髓内酯靶向Na(+)/K(+)- atp酶alpha1可能是一种对抗某些非小细胞肺癌的新方法。
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 alpha1 subunit as a novel target in NSCLC and revealed that alpha1 expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in alpha1 expression in A549 NSCLC cells by anti-alpha1 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 (alpha1beta1, alpha2beta1 and alpha3beta1), most strikingly of alpha1beta1. 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 alpha1. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha1 siRNA 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 alpha1 using specific cardenolides could represent a novel means to combat certain NSCLCs.