Inhibition of Nek2 by small molecules affects proteasome activity.
Inhibition of Nek2 by small molecules affects proteasome activity.
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DOI：
10.1155/2014/273180
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发表时间：
2014
影响因子：
--
通讯作者：
Bearss DJ
中科院分区：
文献类型：
--
作者：
Meng L;Carpenter K;Mollard A;Vankayalapati H;Warner SL;Sharma S;Tricot G;Zhan F;Bearss DJ
背景。Nek2是位于中心体上的丝氨酸/苏氨酸激酶。它通过诱导中心体分离促进细胞周期从G2到M的进程。近期研究表明，Nek2高表达与多发性骨髓瘤患者的耐药相关。材料与方法。为了研究Nek2在硼替佐米耐药中的作用，我们在包括多发性骨髓瘤在内的几种癌细胞系中异位过表达Nek2。Nek2的小分子抑制剂是利用内部化合物库发现的。我们在几种细胞系中测试了抑制剂对蛋白酶体和细胞周期活性的影响。结果。蛋白酶体活性在nek2过表达细胞系中升高。Nek2抑制剂抑制这些癌细胞系的蛋白酶体活性。用这些抑制剂治疗可抑制HeLa细胞中蛋白酶体介导的几种细胞周期调节因子的降解，使其在G2/M中停滞。将这些Nek2抑制剂与硼替佐米联合使用，可以提高硼替佐米体外降低蛋白酶体活性的效果。这些新型Nek2抑制剂治疗成功地减轻了硼替佐米耐药多发性骨髓瘤的耐药性。结论。Nek2在蛋白酶体介导的细胞周期调节和癌细胞对硼替佐米的抗性中起核心作用。综上所述，我们的研究结果将Nek2作为硼替佐米耐药多发性骨髓瘤的治疗靶点。
Background. Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients. Materials and Methods. To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines. Results. Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma. Conclusion. Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.
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影响因子：
4.6
作者：
Ji, JY;Crest, J;Schubiger, G
通讯作者：
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影响因子：
8
作者：
He, JQ;Xu, HG;Hall, RA
通讯作者：
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影响因子：
3.5
作者：
Dinarina, Ana;Santamaria, Patricia G.;Nebreda, Angel R.
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Nebreda, Angel R.
影响因子：
3.3
作者：
Margolis, SS;Perry, JA;Kornbluth, S
通讯作者：
Kornbluth, S
DOI：
10.1006/bbrc.2001.6212
发表时间：
2002-01-18
影响因子：
3.1
作者：
Kim, YH;Choi, JY;Rhee, K
通讯作者：
Rhee, K