Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.
Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.
复制标题
Aurora激酶A介导上皮卵巢癌细胞的迁移和粘附。
作者：
极光激酶A（AURKA）定位于中心体和有丝分裂纺锤体，在那里它介导有丝分裂进程和染色体稳定性。AURKA的过表达在癌症中很常见，导致获得替代的非有丝分裂功能。在本研究中，我们确定了AURKA在调节卵巢癌细胞播散中的新作用，并使用上皮性卵巢癌（EOC）原位异种移植模型评价了AURKA选择性小分子抑制剂alisertib（MLN 8237）单药治疗和与紫杉醇联合治疗的疗效。卵巢癌细胞系用于评估AURKA抑制和过表达对迁移和粘附的影响。药理学或RNAi介导的AURKA抑制显著降低卵巢癌细胞迁移和粘附以及细胞骨架调节蛋白SRC酪氨酸416（pSRCY416）的活化相关磷酸化。相反，AURKA的强制表达导致培养细胞中SRC的迁移、粘附和活化增加。alisertib单药治疗可抑制体内肿瘤生长和播散。此外，alisertib与紫杉醇（一种常用于治疗EOC的药物）联合使用，与单独使用任一种药物相比，对肿瘤生长和扩散的抑制作用更强。总之，这些研究结果支持AURKA通过调节迁移和粘附在EOC传播中的作用。他们还指出了将AURKA抑制剂与紫杉烷类化合物组合作为治疗EOC患者的治疗策略的潜在效用。
Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacologic or RNAi-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRCY416). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared to either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.