Al-Khafaji Ahmed Sk, Davies Michael Pa, Risk Janet M, Marcus Michael W, Koffa Maria, Gosney John R, Shaw Richard J, Field John K, Liloglou Triantafillos
Roy Castle Lung Cancer ResearchProgramme, Department of Molecular and Clinical Cancer Medicine, Instituteof Translational Medicine, University of Liverpool,Liverpool, UK.
Department of Biology, Collage ofScience, University of Baghdad, Baghdad,Iraq.
Br J Cancer. 2017 Feb 28;116(5):592-599. doi: 10.1038/bjc.2016.453. Epub 2017 Jan 17.
Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells.
AURKB mRNA expression was determined by qPCR in 132 frozen NSCLC tissues and nine NSCLC cell lines. Aurora B expression was knocked down in cell lines using multiple shRNA constructs. Barasertib was used to specifically inhibit AURKB activity, determined by the level of H3S10 phosphorylation.
Frequent AURKB mRNA upregulation was observed in NSCLC tissues (P<0.0001), being more prominent in squamous carcinomas (P<0.0001). Aurora B expression in cell lines strongly correlated with sensitivity to both docetaxel (P=0.004) and paclitaxel (P=0.007). Aurora B knockdown derivatives consistently showed a dose-dependent association between low-AURKB expression and resistance to paclitaxel. Specific chemical inhibition of Aurora B activity also demonstrated a strong dose-dependent efficiency in triggering paclitaxel resistance.
Aurora B activity is an important modulator of taxane response in NSCLC cells. This may lead to further insights into taxane sensitivity of NSCLC tumours.
紫杉烷是广泛用于治疗非小细胞肺癌（NSCLC）的有丝分裂毒物，然而，对于这些化合物反应的潜在分子调节因子知之甚少。极光激酶B（AURKB）是有丝分裂纺锤体组装的关键调节因子，先前显示在NSCLC中过表达。在此，我们研究了AURKB表达调节NSCLC细胞中紫杉烷疗效的假说。
通过qPCR测定132例冷冻NSCLC组织和9种NSCLC细胞系中的AURKB mRNA表达。使用多种shRNA构建体在细胞系中敲低极光激酶B表达。使用巴瑞替尼特异性抑制AURKB活性，通过H3S10磷酸化水平来确定。
在NSCLC组织中观察到频繁的AURKB mRNA上调（P<0.0001），在鳞状细胞癌中更明显（P<0.0001）。细胞系中的极光激酶B表达与对多西他赛（P=0.004）和紫杉醇（P=0.007）的敏感性密切相关。极光激酶B敲低衍生物始终显示低AURKB表达与对紫杉醇耐药之间存在剂量依赖性关联。对极光激酶B活性的特异性化学抑制也显示出在引发紫杉醇耐药方面有很强的剂量依赖性效率。
极光激酶B活性是NSCLC细胞中紫杉烷反应的重要调节因子。这可能会进一步深入了解NSCLC肿瘤对紫杉烷的敏感性。
