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Abstract：
Background: Aurora kinase A (AURKA) is a potent oncogene that is often aberrantly expressed during tumorigenesis, and is associated with chemo-resistance in various malignancies. However, the role of AURKA in chemo-resistance remains largely elusive. Methods: The cleavage of AURKA upon viral infection or apoptosis stimuli was assesed by immunoblotting assays in several cancer cells or caspase deficient cell line models. The effect of AURKA cleavage at Asp132 on mitosis was explored by live cell imaging and immunofluorescence staining experiments. The role of Asp132-cleavage of AURKA induced by the chemotherapy drug paclitaxel was investigated using TUNEL, immunohistochemistry assay in mouse tumor xenograft model and patient tissues. Results: The proteolytic cleavage of AURKA at Asp132 commonly occurs in several cancer cell types, regardless of viral infection or apoptosis stimuli. Mechanistically, caspase 3/7/8 cleave AURKA at Asp132, and the Asp132-cleaved forms of AURKA promote cell apoptosis by disrupting centrosome formation and bipolar spindle assembly in metaphase during mitosis. The AURKAD132A mutation blocks the expression of cleaved caspase 3 and EGR1, which leads to reduced therapeutic effects of paclitaxel on colony formation and malignant growth of tumor cells in vitro and in vivo using a murine xenograft model and cancer patients. Conclusions: This study reveals that caspase-mediated AURKAD132 proteolysis is essential for paclitaxel to elicit cell apoptosis and indicates that AURKAD132 is a potential key target for chemotherapy.
摘要：
背景：Aurora激酶A（AURKA）是一种有效的癌基因，在肿瘤发生过程中经常异常表达。并且与各种恶性肿瘤的化学抗性有关。然而,AURKA在化疗耐药中的作用在很大程度上仍然难以捉摸。方法：在几种癌细胞或caspase缺陷细胞系模型中，通过免疫印迹测定法评估了病毒感染或凋亡刺激下AURKA的裂解。通过活细胞成像和免疫荧光染色实验探索Asp132处AURKA裂解对有丝分裂的影响。使用TUNEL研究了化疗药物紫杉醇诱导的AURKA的Asp132裂解的作用，在小鼠肿瘤异种移植模型和患者组织中的免疫组织化学测定。结果：AURKA在Asp132的蛋白水解裂解通常发生在几种癌细胞类型中，无论病毒感染或凋亡刺激。机械上,caspase3/7/8在Asp132处切割AURKA，Asp132切割形式的AURKA通过破坏有丝分裂期间中期的中心体形成和双极纺锤体组装来促进细胞凋亡。AURKAD132A突变阻断裂解的半胱天冬酶3和EGR1的表达，这导致紫杉醇在体外和体内使用鼠异种移植模型和癌症患者对肿瘤细胞集落形成和恶性生长的治疗作用降低。结论：这项研究表明，caspase介导的AURKAD132蛋白水解对于紫杉醇引起细胞凋亡至关重要，并表明AURKAD132是化疗的潜在关键靶标。
