背景：极光激酶 A (AURKA) 是一种强效癌基因，在肿瘤发生过程中经常异常表达，并与多种恶性肿瘤的化疗耐药相关。然而，AURKA 在化疗耐药性中的作用在很大程度上仍然难以捉摸。方法：通过免疫印迹法在几种癌细胞或 caspase 缺陷细胞系模型中评估病毒感染或细胞凋亡刺激时 AURKA 的裂解。通过活细胞成像和免疫荧光染色实验探讨了 AURKA 在 Asp132 处的切割对有丝分裂的影响。使用 TUNEL、免疫组织化学测定法在小鼠肿瘤异种移植模型和患者组织中研究了化疗药物紫杉醇诱导的 AURKA 的 Asp132 裂解的作用。结果：无论病毒感染还是细胞凋亡刺激，AURKA 在 Asp132 处的蛋白水解切割通常发生在几种癌细胞类型中。从机制上讲，Caspase 3/7/8 在 Asp132 处裂解 AURKA，而 Asp132 裂解形式的 AURKA 通过破坏有丝分裂中期的中心体形成和双极纺锤体组装来促进细胞凋亡。 AURKAD132A 突变阻断了 caspase 3 和 EGR1 的表达，从而导致紫杉醇对小鼠异种移植模型和癌症患者的体外和体内肿瘤细胞集落形成和恶性生长的治疗效果降低。结论：这项研究揭示了 caspase 介导的 AURKAD132 蛋白水解对于紫杉醇引发细胞凋亡至关重要，并表明 AURKAD132 是化疗的潜在关键靶标。© 作者。

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.© The author(s).