Zekri Ali, Ghaffari Seyed H, Yaghmaie Marjan, Estiar Mehrdad Asghari, Alimoghaddam Kamran, Modarressi Mohammad Hossein, Ghavamzadeh Ardeshir
Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Mol Neurobiol. 2016 Apr;53(3):1808-1823. doi: 10.1007/s12035-015-9139-9. Epub 2015 Mar 11.
Aurora kinase B (AURKB), a crucial regulator of malignant mitosis, is involved in chromosome segregation and cytokinesis. AZD1152-HQPA is a selective inhibitor for AURKB activity and currently bears clinical assessment for several malignancies. However, the effect of this drug still needs to be elucidated in neurological malignancies. In this study, we investigated the restrictive potentials of AZD1152-HQPA in U87MG and SK-N-MC. AZD1152-HQPA treatment resulted in growth arrest, modification of cell cycle, and inhibition of colony formation in both cell lines. Furthermore, lower concentrations of AZD1152-HQPA profoundly induced apoptosis in U87GM (p53/p73 wild type) cells in parallel with an upregulation of p53 and its target genes BAX, BAD, APAF1, and PUMA. But remarkably, SK-N-MC (p53/p73 double null) responded to AZD1152-HQPA at much higher concentrations with an upregulation of genes involved in cell cycle progression, induction of excessive endoreduplication, and polyploidy rather than apoptosis. Although SK-N-MC was resistant to AZD1152-HQPA, we did not find a mutation in the coding sequence of Aurora B gene or overexpressions of ABCG2 and ABCB1 as reported previously to be resistance mechanisms. However, our results suggest that p53/p73 status could be an important mechanism for the type of response and resistance of the tumor cells to AZD1152-HQPA. Collectively, inhibition of Aurora kinase B differentially induced cell death and polyploidy via DNA damage response pathways, depending on the status of p53/p73. We suggest p53/p73 could be a key regulator of sensitivity to AZD1152-HQPA and their status should be explored in clinical response to this ongoing drug in clinical trials.
极光激酶B（AURKB）是恶性有丝分裂的关键调节因子，参与染色体分离和胞质分裂。AZD1152-HQPA是一种AURKB活性的选择性抑制剂，目前正在对多种恶性肿瘤进行临床评估。然而，这种药物在神经恶性肿瘤中的作用仍有待阐明。在本研究中，我们研究了AZD1152-HQPA对U87MG和SK-N-MC细胞的抑制潜力。AZD1152-HQPA处理导致这两种细胞系生长停滞、细胞周期改变和集落形成受到抑制。此外，较低浓度的AZD1152-HQPA可显著诱导U87GM（p53/p73野生型）细胞凋亡，同时上调p53及其靶基因BAX、BAD、APAF1和PUMA。但值得注意的是，SK-N-MC（p53/p73双缺失）细胞对AZD1152-HQPA的反应浓度要高得多，其细胞周期进程相关基因上调，诱导过度核内复制和多倍体形成，而非凋亡。尽管SK-N-MC对AZD1152-HQPA耐药，但我们并未在极光B基因编码序列中发现突变，也未发现如先前报道的ABCG2和ABCB1过表达作为耐药机制。然而，我们的结果表明，p53/p73状态可能是肿瘤细胞对AZD1152-HQPA反应类型和耐药性的重要机制。总的来说，抑制极光激酶B通过DNA损伤反应途径差异性地诱导细胞死亡和多倍体形成，这取决于p53/p73的状态。我们认为p53/p73可能是对AZD1152-HQPA敏感性的关键调节因子，在该药物正在进行的临床试验的临床反应中应探索其状态。
