摘要
背景:奥罗拉激酶在肿瘤治疗中是可行的靶点。 目的:探讨人肝癌细胞对alisertib(ALS)的蛋白质组学反应和确定ALS的分子靶点,我们研究了ALS影响HepG2细胞的增殖,细胞周期,细胞自噬,细胞凋亡和化疗敏感性。 方法:基于定量蛋白质组学用氨基酸在细胞培养(SILAC)研究稳定的同位素标记,评估ALS蛋白质组学反应。用流式细胞仪检测细胞周期分布和细胞凋亡,流式细胞术和共聚焦显微镜测定自噬。 结果:我们的SILAC蛋白质组研究表明ALS调节914蛋白的表达,上调407分子和507分子和下调HepG2细胞。信号网络分析(IPA)和KEGG通路分析,发现ALS调节146和32信号通路,分别与细胞的存活、细胞程序性死亡和营养能量代谢相关。随后的验证实验表明,通过调节关键的细胞周期调控因子的表达,ALS明显地阻滞G2 / M期的HepG2细胞,并导致非整倍体的积累。 ALS通过雷帕霉素(mTOR)信号通路磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/哺乳类动物靶点,诱导了依赖浓度和时间的标记的自噬。自噬的抑制促进了ALS的促凋亡作用,表明ALS诱导的自噬的细胞保护作用。ALS增加HepG2细胞对顺铂和阿霉素的化疗敏感性。 结论:通过PI3K/Akt/mTOR-介导通路,ALS诱导HepG2细胞自噬和细胞周期阻滞。抑制自噬可促进ALS的抗癌作用和提高肝癌HepG2细胞的化疗敏感性。
关键词: 肝癌,HepG2细胞,奥罗拉激酶A,alisertib,细胞周期,程序性细胞死亡,SILAC,蛋白质组学。
Current Cancer Drug Targets
Title:Inhibition of Aurora A Kinase by Alisertib Induces Autophagy and Cell Cycle Arrest and Increases Chemosensitivity in Human Hepatocellular Carcinoma HepG2 Cells
Volume: 17 Issue: 4
关键词: 肝癌,HepG2细胞,奥罗拉激酶A,alisertib,细胞周期,程序性细胞死亡,SILAC,蛋白质组学。
摘要: Background: Aurora A kinase represent a feasible target in cancer therapy.
Objective: To evaluate the proteomic response of human liver carcinoma cells to alisertib (ALS) and identify the molecular targets of ALS, we examined the effects of ALS on the proliferation, cell cycle, autophagy, apoptosis, and chemosensitivity in HepG2 cells. Method: The stable-isotope labeling by amino acids in cell culture (SILAC) based quantitative proteomic study was performed to evaluate the proteomic response to ALS. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy. Results: Our SILAC proteomic study showed that ALS regulated the expression of 914 proteins, with 407 molecules being up-regulated and 507 molecules being down-regulated in HepG2 cells. Ingenuity pathway analysis (IPA) and KEGG pathway analysis identified 146 and 32 signaling pathways were regulated by ALS, respectively, which were associated with cell survival, programmed cell death, and nutrition-energy metabolism. Subsequently, the verification experiments showed that ALS remarkably arrested HepG2 cells in G2/M phase and led to an accumulation of aneuploidy via regulating the expression of key cell cycle regulators. ALS induced a marked autophagy in a concentration- and time-dependent manner via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Autophagy inhibition promoted the pro-apoptotic effect of ALS, indicating a cyto-protective role of ALS-induced autophagy. ALS increased the chemosensitivity of HepG2 cells to cisplatin and doxorubicin. Conclusion: Taken together, ALS induces autophagy and cell cycle arrest in HepG2 cells via PI3K/Akt/mTOR-mediated pathway. Autophagy inhibition may promote the anticancer effect of ALS and sensitize the chemotherapy in HepG2 cells.Export Options
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Cite this article as:
Inhibition of Aurora A Kinase by Alisertib Induces Autophagy and Cell Cycle Arrest and Increases Chemosensitivity in Human Hepatocellular Carcinoma HepG2 Cells, Current Cancer Drug Targets 2017; 17 (4) . https://dx.doi.org/10.2174/1568009616666160630182344
DOI https://dx.doi.org/10.2174/1568009616666160630182344 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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