Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.
Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells.
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DOI：
10.2147/dddt.s74062
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Zhou SF
中科院分区：
文献类型：
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作者：
Ding YH;Zhou ZW;Ha CF;Zhang XY;Pan ST;He ZX;Edelman JL;Wang D;Yang YX;Zhang X;Duan W;Yang T;Qiu JX;Zhou SF
卵巢癌是女性的主要杀手，晚期卵巢癌没有治愈方法。Alisertib（ALS）是一种选择性极光激酶A（AURKA）抑制剂，已显示出有效的抗癌作用，并正在临床研究中用于治疗晚期实体瘤和血液恶性肿瘤。然而，ALS在卵巢癌治疗中的作用仍不清楚。本研究探讨了ALS对人上皮性卵巢癌SKOV 3和OVCAR 4细胞生长、凋亡、自噬和上皮间质转化（EMT）的影响及其潜在机制。我们的对接研究表明，ALS，MLN 8054和VX-680优先结合AURKA超过AURKB通过氢键形成，电荷相互作用和π-π堆积。ALS对SKOV 3和OVCAR 4细胞具有强效的生长抑制、促凋亡、促自噬和EMT抑制作用。ALS使SKOV 3和OVCAR 4细胞阻滞于G2/M期，并以浓度依赖性方式诱导SKOV 3和OVCAR 4细胞凋亡和自噬。ALS抑制磷脂酰肌醇3-激酶/蛋白激酶B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）和p38丝裂原活化蛋白激酶通路，但激活5′-AMP依赖性激酶，如其磷酸化改变所示，有助于ALS的促自噬活性。自噬的调节改变了SKOV 3和OVCAR 4细胞的基础和ALS诱导的凋亡。此外，ALS通过恢复E-钙粘蛋白和N-钙粘蛋白之间的平衡来抑制两种细胞系中的EMT样表型。ALS下调sirtuin 1和前B细胞集落增强因子（PBEF/visfatin）的表达水平，并抑制AURKA的磷酸化。这些结果表明，ALS通过G2/M期阻滞细胞周期，促进细胞凋亡和自噬，但通过磷脂酰肌醇3-激酶/Akt/mTOR介导的途径和sirtuin 1介导的途径抑制EMT。需要进一步研究来验证ALS治疗卵巢癌的有效性和安全性。
Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5′-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer.