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NEK2 induces autophagy-mediated bortezomib resistance by stabilizing Beclin-1 in multiple myeloma.
Molecular Oncology ( IF 6.6 ) Pub Date : 2020-01-29 , DOI: 10.1002/1878-0261.12641
Jiliang Xia 1, 2 , Yanjuan He 1 , Bin Meng 2 , Shilian Chen 2 , Jingyu Zhang 2 , Xuan Wu 2 , Yinghong Zhu 2 , Yi Shen 3, 4 , Xiangling Feng 5 , Yongjun Guan 2 , Chunmei Kuang 2 , Jiaojiao Guo 2 , Qian Lei 2 , Yangbowen Wu 5 , Gang An 6 , Guancheng Li 2 , Lugui Qiu 6 , Fenghuang Zhan 4 , Wen Zhou 1, 2
Affiliation  

NEK2 is associated with drug resistance in multiple cancers. Our previous studies indicated that high NEK2 confers inferior survival in multiple myeloma (MM); thus, a better understanding of the mechanisms by which NEK2 induces drug resistance in MM is required. In this study, we discovered that NEK2 enhances MM cell autophagy, and a combination of autophagy inhibitor chloroquine (CQ) and chemotherapeutic bortezomib (BTZ) significantly prevents NEK2-induced drug resistance in MM cells. Interestingly, NEK2 was found to bind and stabilize Beclin-1 protein but did not affect its mRNA expression and phosphorylation. Moreover, autophagy enhanced by NEK2 was significantly prevented by knockdown of Beclin-1 in MM cells, suggesting that Beclin-1 mediates NEK2-induced autophagy. Further studies demonstrated that Beclin-1 ubiquitination is decreased through NEK2 interaction with USP7. Importantly, knockdown of Beclin-1 sensitized NEK2-overexpressing MM cells to BTZ in vitro and in vivo. In conclusion, we identify a novel mechanism whereby autophagy is activated by the complex of NEK2/USP7/Beclin-1 in MM cells. Targeting the autophagy signaling pathway may provide a promising therapeutic strategy to overcome NEK2-induced drug resistance in MM.

中文翻译:

NEK2 通过稳定多发性骨髓瘤中的 Beclin-1 来诱导自噬介导的硼替佐米耐药性。

NEK2 与多种癌症的耐药性相关。我们之前的研究表明,高 NEK2 会导致多发性骨髓瘤 (MM) 患者的生存率较差;因此,需要更好地了解 NEK2 诱导 MM 耐药的机制。在这项研究中,我们发现NEK2增强MM细胞自噬,自噬抑制剂氯喹(CQ)和化疗药物硼替佐米(BTZ)的组合可显着预防NEK2诱导的MM细胞耐药性。有趣的是,NEK2被发现可以结合并稳定Beclin-1蛋白,但不影响其mRNA表达和磷酸化。此外,在MM细胞中敲低Beclin-1可显着阻止NEK2增强的自噬,这表明Beclin-1介导NEK2诱导的自噬。进一步的研究表明,Beclin-1 泛素化通过 NEK2 与 USP7 的相互作用而降低。重要的是,在体外和体内,Beclin-1 的敲低使 NEK2 过表达的 MM 细胞对 BTZ 敏感。总之,我们确定了 MM 细胞中 NEK2/USP7/Beclin-1 复合物激活自噬的新机制。靶向自噬信号通路可能为克服 NEK2 诱导的 MM 耐药性提供一种有前景的治疗策略。
更新日期:2020-01-19
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