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Theranostics

Theranostics

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Caspase-mediated AURKA cleavage at Asp132 is essential for paclitaxel to elicit cell apoptosis

Published:17 June 2024 DOI: 10.7150/thno.97842 PMID: 38994036
Xiaoting Chen,?Shujuan Du,?Yulin Zhang,?Ke Peng,?Lina Liu,?Ting Wang,?Hao Zhang,?Shen Cai,?Caixia Zhu,?Youhai Li,?Wen Tuo,?Yuyan Wang,?Fang Wei,?Qiliang Cai

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.

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Z-DEVD-FMK 210344-95-9 C30H41FN4O12 213 suppliers $28.00-$4023.90
Z-DEVD-FMK 210344-95-9 C30H41FN4O12 213 suppliers $28.00-$4023.90
Z-DEVD-FMK 210344-95-9 C30H41FN4O12 213 suppliers $28.00-$4023.90
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Z-Vad-fmk, non-methylated 161401-82-7 C21H28FN3O7 89 suppliers $70.00-$3200.00
Z-Vad-fmk, non-methylated 161401-82-7 C21H28FN3O7 89 suppliers $70.00-$3200.00
Z-Vad-fmk, non-methylated 161401-82-7 C21H28FN3O7 89 suppliers $70.00-$3200.00

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