单位：[1]Experimental Medicine Center of Tongji Hospital,Tongji Medical College,Huazhong University of Science & Technology,Wuhan 430030,China华中科技大学同济医学院附属同济医院科研平台[2]Department of Pediatrics of Tongji Hospital,Tongji Medical College,Huazhong University of Science & Technology,Wuhan 430030,China.华中科技大学同济医学院附属同济医院儿科学系[3]Department of Pediatric Surgery of Tongji Hospital,Tongji Medical College,Huazhong University of Science & Technology,Wuhan 430030,China.华中科技大学同济医学院附属同济医院儿科学系外科学系小儿外科
Background Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies including neuroblastoma. Small molecule inhibitors of AURKA have shown potential, but still not as good as expected effects in clinical trials. Little is known about this underlying mechanism. Here, we evaluated the inhibitory effects of AURKA inhibitor MLN8237 on neuroblastoma cells to understand the potential mechanisms responsible for tumor therapy. Methods MLN8237 treatment on neuroblastoma cell line IMR32 was done and in vivo inhibitory effects were investigated using tumor xenograft model. Cellular senescence was evaluated by senescence-associated beta-gal Staining assay. Flow cytometry was used to tested cell cycle arrest and cell apoptosis. Senescence-associated signal pathways were detected by western blot. CD133 microbeads and microsphere formation were used to separate and enrich CD133(+) cells. AURKA small interfering RNA transfection was carried to downregulate AURKA level. Finally, the combination of MLN8237 treatment with AURKA small interfering RNA transfection were adopted to evaluate the inhibitory effect on neuroblastoma cells. Results We demonstrate that MLN8237, an inhibitor of AURKA, induces the neuroblastoma cell line IMR32 into cellular senescence and G2/M cell phase arrest. Inactivation of AURKA results in MYCN destabilization and inhibits cell growth in vitro and in a mouse model. Although MLN8237 inhibits AURKA kinase activity, it has almost no inhibitory effect on the AURKA protein level. By contrast, MLN8237 treatment leads to abnormal high expression of AURKA in vitro and in vivo. Knockdown of AURKA reduces cell survival. The combination of MLN8237 with AURKA small interfering RNA results in more profound inhibitory effects on neuroblastoma cell growth. Moreover, MLN8237 treatment followed by AURKA siRNA forces senescent cells into apoptosis via suppression of the Akt/Stat3 pathway. Conclusions The effect of AURKA-targeted inhibition of tumor growth plays roles in both the inactivation of AURKA activity and the decrease in the AURKA protein expression level.
基金：
General Programs from the National Natural Sci-ence Foundation of China [81472706, 81874187]
第一作者单位：[1]Experimental Medicine Center of Tongji Hospital,Tongji Medical College,Huazhong University of Science & Technology,Wuhan 430030,China
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推荐引用方式(GB/T 7714)：
yang yan,ding lili,zhou qi,et al.Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells[J].CANCER CELL INTERNATIONAL.2020,20(1):doi:10.1186/s12935-019-1072-y.
APA：
yang,yan,ding,lili,zhou,qi,fen,li,cao,yuhua...&liu,aiguo.(2020).Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells.CANCER CELL INTERNATIONAL,20,(1)
MLA：
yang,yan,et al."Silencing of AURKA augments the antitumor efficacy of the AURKA inhibitor MLN8237 on neuroblastoma cells".CANCER CELL INTERNATIONAL 20..1(2020)
