Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells
| Autor: | Zhi Wei Zhou, Wei Duan, Shu-Feng Zhou, Si Jia He, Zhi Xu He, Tianxin Yang, Li Ping Shu, Xueji Zhang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteomics Ribosomal Proteins Cancer Research Aurora inhibitor Antineoplastic Agents Apoptosis Cell Cycle Proteins HL-60 Cells Biology Transfection 03 medical and health sciences 0302 clinical medicine Aurora kinase medicine Autophagy Aurora Kinase B Humans Danusertib Molecular Targeted Therapy Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Leukemia Dose-Response Relationship Drug Kinase Ribosomal Protein S6 Kinases 70-kDa medicine.disease Cell biology Mitochondria G2 Phase Cell Cycle Checkpoints 030104 developmental biology Oncology 030220 oncology & carcinogenesis Benzamides Cancer research Pyrazoles RNA Interference Apoptosis Regulatory Proteins K562 Cells Signal Transduction |
| Zdroj: | Cancer letters. 382(2) |
| ISSN: | 1872-7980 |
| Popis: | Leukemia is a common malignancy of blood cells with poor prognosis in many patients. Aurora kinases, a family of serine/threonine kinases, play a key role in regulating cell division and mitosis and are linked to tumorigenesis, metastasis, and poor prognosis in many human cancers including leukemia and lymphoma. Danusertib (Danu) is a pan-inhibitor of Aurora kinases with few data available in leukemia therapy. This study aimed to identify new molecular targets for Aurora kinase inhibition in human leukemia cells using quantitative proteomic analysis followed by verification experiments. There were at least 2932 proteins responding to Danu treatment, including AURKB, p70S6K, and RPL15, and 603 functional proteins and 245 canonical signaling pathways were involved in regulating cell proliferation, metabolism, apoptosis, and autophagy. The proteomic data suggested that Danu-regulated RPL15 signaling might contribute to the cancer cell killing effect. Our verification experiments confirmed that Danu negatively regulated AURKB/p70S6K/RPL15 axis with the involvement of PI3K/Akt/mTOR, AMPK, and p38 MAPK signaling pathways, leading to the induction of apoptosis and autophagy in human leukemia cells. Further studies are warranted to verify the feasibility via targeting AURKB/p70S6K/RPL15 axis for leukemia therapy. |
| Databáze: | OpenAIRE |
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