Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma
Inhibition of Aurora-A results in increased cell death in 3-dimensional culture microenvironment, reduced migration and is associated with enhanced radiosensitivity in human nasopharyngeal carcinoma
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抑制 Aurora-A 会导致 3 维培养微环境中的细胞死亡增加、迁移减少，并与人鼻咽癌的放射敏感性增强相关
DOI：
10.4161/cbt.8.15.8958
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
--
作者：
Wan, Xiang-Bo;Fan, Xin-Juan;Liu, Quentin
有丝分裂相关的Aurora-A激酶在多种癌中扩增。Aurora-A的过表达有助于肿瘤的发生和疾病的进展，并且已经成为设计抗癌药物的有吸引力的分子靶标。本研究探讨Aurora-A选择性小分子抑制剂VX-680对鼻咽癌CNE-2细胞的作用。我们发现VX-680抑制了二维培养的NPC CNE-2细胞的增殖并诱导其凋亡。此外，CNE-2细胞在三维（3-D）基质培养微环境中形成肿瘤样细胞团，并且VX-680预处理指定时间后，肿瘤团形成可被削弱。类似地，当将VX-680加入到预先形成的3-D CNE-2肿瘤块中时，紧密空间的肿瘤块经历了明显的凋亡细胞死亡，并因此解离成单个的死细胞，如通过裂解的胱天蛋白酶-3免疫荧光测定所检测到的。迁移实验显示VX-680呈剂量依赖性地降低鼻咽癌CNE-2细胞的迁移能力。我们进一步研究发现，X射线照射和VX-680均能上调p53蛋白表达水平，使细胞周期阻滞于G（2）/M期，使鼻咽癌CNE-2细胞对放射线敏感，并有效地导致细胞死亡。综上所述，我们的数据表明Aurora-A小分子抑制剂VX-680有效地破坏肿瘤形成并诱导凋亡，减少细胞迁移并增强放射敏感性，为人类NPC提供了有希望的治疗剂。
Mitosis related Aurora-A kinase is amplified in a variety of carcinomas. Overexpression of Aurora-A contributes to tumorigenesis and disease progression, and has emerged as an attractive molecular target for the design of anticancer drugs. In this study, we investigated the function of Aurora-A selectively small molecule inhibitor VX-680 in nasopharyngeal carcinoma (NPC) CNE-2 cells. We found that VX-680 suppressed proliferation and induced apoptosis of 2-dimensional (2-D) cultured NPC CNE-2 cells. Moreover, CNE-2 cells formed a tumor-like cell mass in 3-dimensional (3-D) matrix culture microenvironment, and the tumor mass formation could be impaired when pretreated with VX-680 for indicated time. Similarly, when adding VX-680 to preformed 3-D CNE-2 tumor mass, the tight spatial tumor mass experienced apparent apoptotic cell death and consequently dissociated into individual dead cells, as detected by cleaved Caspase-3 immunofluorescence assay. The migration assay showed that VX-680 decreased NPC CNE-2 cell migration ability in a dose-dependent manner. Our further study revealed that X-ray irradiation and VX-680 upregulated p53 expression level as well as arrested cell cycle in G(2)/M, sensitized NPC CNE-2 cells to radiation and effectively resulted in cell death. In summary, our data indicated that Aurora-A small molecule inhibitor VX-680, potently destructed tumor formation and induced apoptosis, reduced cell migration and enhanced radiosensitivity, offering a promising therapeutic agent for human NPC.