Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma, and is a potential chemotherapeutic target in gliomas
Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma, and is a potential chemotherapeutic target in gliomas
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DOI：
10.4161/cc.11.3.18996
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发表时间：
2012-02-01
期刊：
影响因子：
4.3
通讯作者：
Poisson, Laila M.
中科院分区：
文献类型：
--
作者：
Lehman, Norman L.;O'Donnell, James P.;Poisson, Laila M.
Aurora A对于有丝分裂至关重要，并且在多种肿瘤中过表达。它的过表达转化培养的细胞，它的过表达和敲低都会引起基因组的不稳定性。在转基因小鼠中，Aurora A单倍不足，而不是过度表达，导致恶性肿瘤形成增加。因此，Aurora A似乎具有肿瘤促进和肿瘤抑制功能。在这里，我们报告的极光A蛋白，定量蛋白质印迹法测定，差异表达的主要胶质瘤类型的谱系特异性模式。Aurora A蛋白在WHO II级少突胶质细胞瘤（n = 16）和III级间变性少突胶质细胞瘤（n = 16）中的水平通常较低，与对照癫痫脑组织（n = 11）相似。相比之下，毛细胞型星形细胞瘤（n = 6）和室管膜瘤（n = 12）表达高Aurora A水平。在II级至III级星形细胞瘤（分别为n = 7，n = 14）和IV级胶质母细胞瘤（n = 31）中，Aurora A蛋白随着肿瘤级别的升高而升高。我们还发现Aurora A的表达在培养的胶质母细胞瘤细胞中由缺氧诱导，并且在胶质母细胞瘤肿瘤的缺氧区域中过表达。回顾性Kaplan-Meier分析显示，定量蛋白质印迹法测定的较低Aurora A蛋白（n = 31）和实时定量RT-PCR法测定的Aurora A mRNA水平（n = 58）均与胶质母细胞瘤患者生存率较差显著相关。此外，我们报告了选择性Aurora A抑制剂MLN 8237对胶质母细胞瘤细胞具有强效细胞毒性，并且MLN 8237的细胞毒性可通过电离辐射增强。MLN 8237似乎还诱导胶质母细胞瘤细胞衰老和分化。因此，除了与胶质母细胞瘤的存活率显著相关外，Aurora A还是治疗胶质母细胞瘤和可能的其他胶质肿瘤的潜在新药靶点。
Aurora A is critical for mitosis and is overexpressed in several neoplasms. Its overexpression transforms cultured cells, and both its overexpression and knockdown cause genomic instability. In transgenic mice, Aurora A haploinsufficiency, not overexpression, leads to increased malignant tumor formation. Aurora A thus appears to have both tumor-promoting and tumor-suppressor functions. Here, we report that Aurora A protein, measured by quantitative western blotting, is differentially expressed in major glioma types in lineage-specific patterns. Aurora A protein levels in WHO grade II oligodendrogliomas (n = 16) and grade III anaplastic oligodendrogliomas (n = 16) are generally low, similar to control epilepsy cerebral tissue (n = 11). In contrast, pilocytic astrocytomas (n = 6) and ependymomas (n = 12) express high Aurora A levels. Among grade II to grade III astrocytomas (n = 7, n = 14, respectively) and grade IV glioblastomas (n = 31), Aurora A protein increases with increasing tumor grade. We also found that Aurora A expression is induced by hypoxia in cultured glioblastoma cells and is overexpressed in hypoxic regions of glioblastoma tumors. Retrospective Kaplan-Meier analysis revealed that both lower Aurora A protein measured by quantitative western blot (n = 31) and Aurora A mRNA levels measured by real-time quantitative RT-PCR (n = 58) are significantly associated with poorer patient survival in glioblastoma. Furthermore, we report that the selective Aurora A inhibitor MLN8237 is potently cytotoxic to glioblastoma cells, and that MLN8237 cytotoxicty is potentiated by ionizing radiation. MLN8237 also appeared to induce senescence and differentiation of glioblastoma cells. Thus, in addition to being significantly associated with survival in glioblastoma, Aurora A is a potential new drug target for the treatment of glioblastoma and possibly other glial neoplasms.