Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells
| العنوان: | Inhibition of mitotic kinase Aurora suppresses Akt-1 activation and induces apoptotic cell death in all-trans retinoid acid-resistant acute promyelocytic leukemia cells |
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| المؤلفون: | Zi Jie Long, Shan Huang, Duo Rong Xu, Quentin Liu, Jia-Jie Chen, Zheng Zhi Zou, Dong Jun Lin, Juan Li |
| المصدر: | Journal of Translational Medicine, Vol 9, Iss 1, p 74 (2011) Journal of Translational Medicine |
| بيانات النشر: | BMC, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Acute promyelocytic leukemia, Aurora inhibitor, Mitosis, lcsh:Medicine, Apoptosis, Tretinoin, Spindle Apparatus, Biology, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Piperazines, Small Molecule Libraries, Promyelocytic leukemia protein, Aurora kinase, Leukemia, Promyelocytic, Acute, Aurora Kinases, Cell Line, Tumor, medicine, Humans, Annexin A5, Protein kinase B, Protein Kinase Inhibitors, Cell Proliferation, Medicine(all), Cell Nucleus, Membrane Potential, Mitochondrial, Cell growth, Biochemistry, Genetics and Molecular Biology(all), Research, lcsh:R, Cell Differentiation, General Medicine, Cell cycle, medicine.disease, Cell biology, Enzyme Activation, Drug Resistance, Neoplasm, Caspases, Cancer research, biology.protein, Proto-Oncogene Proteins c-akt, medicine.drug, Propidium |
| الوصف: | Background Aurora kinase ensures accurate chromosome segregation during cell cycle, maintaining genetic integrity in cell division. VX-680, a small-molecule Aurora kinase inhibitor, interferes with mitotic entry and formation of bipolar spindles. Here, we evaluated VX-680 as a potential agent for treatment of all-trans retinoid acid (ATRA)-resistant acute promyelocytic leukemia (APL) in vitro. Methods CD11b expression was utilized to assess cell differentiation by flow cytometry. Immunofluorescence staining was conducted to analyze formation of cell monopolar spindle. Cell proliferation was evaluated by MTT assay. Sub-G1 population and Annexin V/PI staining were used to measure cell apoptosis. Hoechst 33342 staining was applied for identifying morphological changes in nucleus of apoptotic cell. Aurora-A (Aur-A) activation and the signaling pathways involved in apoptosis were detected by Western blot. JC-1 probe was employed to measure mitochondrial depolarization. Results VX-680 inhibited Aur-A by reducing autophosphorylation at the activation site, Thr288, accompanied by producing monopolar mitotic spindles in APL cell line NB4-R2 that was resistant to ATRA. In addition, we found that VX-680 inhibited cell proliferation as assessed by MTT assay. Flow cytometry showed that VX-680 led to apoptotic cell death in both dose- and time-dependent manners by either Sub-G1 or Annexin V/PI analysis. Hoechst 33342 staining represented typical apoptotic cells with nuclear fragmentation in VX-680 treated cells. Importantly, VX-680 inhibition of Aurora kinase suppressed Akt-1 activation and induced mitochondrial depolarization, which eventually resulted in apoptosis by activation of caspase pathway, as indicated by increasing proteolytic cleavage of procaspase-3 and poly ADP ribose polymerase (PARP) in NB4-R2 cells. Conclusions Our study suggested potential clinical use of mitotic Aurora kinase inhibitor in targeting ATRA-resistant leukemic cells. |
| اللغة: | English |
| تدمد: | 1479-5876 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6f7f622c409da7ce01f3750ae7b0299b http://www.translational-medicine.com/content/9/1/74 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6f7f622c409da7ce01f3750ae7b0299b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14795876 |
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