Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, PR China; Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, PR China.
EBioMedicine. 2017 Dec;26:100-111. doi: 10.1016/j.ebiom.2017.10.030. Epub 2017 Nov 3.
Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers. In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients. Depleting of Aurora B blunted the malignant phenotypes in ESCC cells. Importantly, we demonstrated that a natural compound, deguelin, has a profound anti-tumor effect on ESCC via inhibiting Aurora B activity. Deguelin potently inhibited in vitro Aurora B kinase activity. The in silico docking study further indicated that deguelin was docked into the ATP-binding pocket of Aurora B. Inhibition of Aurora B activity attenuated growth of ESCC cells, resulted in G2/M cell cycle arrest, polyploidy cells formation, and apoptosis induction. Knocking down of Aurora B decreased the sensitivity of ESCC cells to deguelin. The in vivo results showed that deguelin blocked the phosphorylation of histone H3 and inhibited the growth of ESCC tumor xenografts. Overall, we identified deguelin as an effective Aurora B inhibitor, which deserves further studies in other animal models and ESCC treatment.
极光激酶 B 已成为有丝分裂的关键调节因子，极光激酶 B 活性的失调与人类癌症的发生和发展密切相关。在本研究中，我们发现极光激酶 B 在人食管鳞状细胞癌（ESCC）中过度表达，极光 B 蛋白水平高与 ESCC 患者的总生存率降低有关。敲低 Aurora B 可减弱 ESCC 细胞的恶性表型。重要的是，我们证明了一种天然化合物，裂环烯醚萜醇，通过抑制 Aurora B 活性对 ESCC 具有显著的抗肿瘤作用。裂环烯醚萜醇能有效地抑制体外 Aurora B 激酶活性。计算机对接研究进一步表明，裂环烯醚萜醇与 Aurora B 的 ATP 结合口袋结合。抑制 Aurora B 活性可减弱 ESCC 细胞的生长，导致 G2/M 细胞周期停滞、多倍体细胞形成和凋亡诱导。敲低 Aurora B 可降低 ESCC 细胞对裂环烯醚萜醇的敏感性。体内结果表明，裂环烯醚萜醇可阻断组蛋白 H3 的磷酸化，并抑制 ESCC 肿瘤异种移植物的生长。总的来说，我们确定裂环烯醚萜醇是一种有效的 Aurora B 抑制剂，值得在其他动物模型和 ESCC 治疗中进一步研究。
