Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells
Inhibition of Aurora kinases induces apoptosis and autophagy via AURKB/p70S6K/RPL15 axis in human leukemia cells
复制标题
抑制极光激酶可通过人白血病细胞中的 AURKB/p70S6K/RPL15 轴诱导细胞凋亡和自噬。
DOI：
10.1016/j.canlet.2016.08.016
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发表时间：
2016-11-28
期刊：
影响因子：
9.7
通讯作者：
Zhou, Shu-Feng
中科院分区：
文献类型：
--
作者：
He, Si-Jia;Shu, Li-Ping;Zhou, Shu-Feng
白血病是一种常见的血细胞恶性肿瘤，许多患者预后较差。Aurora激酶是一个丝氨酸/苏氨酸激酶家族，在调节细胞分裂和有丝分裂中起关键作用，并与包括白血病和淋巴瘤在内的许多人类癌症的肿瘤发生、转移和不良预后有关。Danusertib （Danu）是一种泛型Aurora激酶抑制剂，用于白血病治疗的数据很少。本研究旨在通过定量蛋白质组学分析和验证实验，确定人类白血病细胞中极光激酶抑制的新分子靶点。至少有2932个蛋白对Danu处理有反应，包括AURKB、p70S6K和RPL15, 603个功能蛋白和245个典型信号通路参与调节细胞增殖、代谢、凋亡和自噬。蛋白质组学数据表明，danu调控的RPL15信号可能有助于癌细胞的杀伤作用。我们的验证实验证实，Danu负调控AURKB/p70S6K/RPL15轴，参与PI3K/Akt/mTOR、AMPK和p38 MAPK信号通路，诱导人白血病细胞凋亡和自噬。需要进一步的研究来验证通过靶向AURKB/p7056K/RPL15轴治疗白血病的可行性。2016爱思唯尔爱尔兰有限公司版权所有。
Leukemia is a common malignancy of blood cells with poor prognosis in many patients. Aurora kinases, a family of serine/threonine kinases, play a key role in regulating cell division and mitosis and are linked to tumorigenesis, metastasis, and poor prognosis in many human cancers including leukemia and lymphoma. Danusertib (Danu) is a pan-inhibitor of Aurora kinases with few data available in leukemia therapy. This study aimed to identify new molecular targets for Aurora kinase inhibition in human leukemia cells using quantitative proteomic analysis followed by verification experiments. There were at least 2932 proteins responding to Danu treatment, including AURKB, p70S6K, and RPL15, and 603 functional proteins and 245 canonical signaling pathways were involved in regulating cell proliferation, metabolism, apoptosis, and autophagy. The proteomic data suggested that Danu-regulated RPL15 signaling might contribute to the cancer cell killing effect. Our verification experiments confirmed that Danu negatively regulated AURKB/p70S6K/RPL15 axis with the involvement of PI3K/Akt/mTOR, AMPK, and p38 MAPK signaling pathways, leading to the induction of apoptosis and autophagy in human leukemia cells. Further studies are warranted to verify the feasibility via targeting AURKB/p7056K/RPL15 axis for leukemia therapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.