The NEDD4-1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
The NEDD4-1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma
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NEDD4-1 E3 泛素连接酶：多发性骨髓瘤中硼替佐米敏感性的潜在分子靶标
DOI：
10.1002/ijc.32615
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发表时间：
2019-08-24
影响因子：
6.4
通讯作者：
Cai, Zhen
中科院分区：
文献类型：
--
作者：
Huang, Xi;Gu, Huiyao;Cai, Zhen
E3泛素连接酶主要决定泛素-蛋白酶体系统的底物特异性，并在多发性骨髓瘤（MM）对硼替佐米的耐药性中发挥重要作用。神经前体细胞表达的发育下调基因4-1（NEDD 4 -1，也称为NEDD 4）是E3连接酶NEDD 4家族的创始成员，参与癌细胞的增殖、迁移、侵袭和药物敏感性。在本研究中，我们研究了NEDD 4 -1在MM细胞中的作用，并探讨了其潜在的机制。临床上，NEDD 4 -1低表达与MM患者的不良预后有关。在功能上，NEDD 4 -1敲低（KD）导致MM细胞在体外和体内对硼替佐米耐药。NEDD 4 -1的过表达（OE），而不是酶死亡的NEDD 4 -1-C867 S突变体，具有相反的效果。此外，NEDD 4 -1 KD细胞中NEDD 4 -1的过表达使细胞在加回拯救实验中对硼替佐米重新敏感。机制上，pAkt-Ser 473水平和Akt信号传导分别通过NEDD 4 -1 KD和OE升高和降低。NEDD 4 -1泛素化Akt并靶向pAkt-Ser 473用于蛋白酶体降解。更重要的是，在用Akt抑制剂处理后，NEDD 4 -1 KD诱导的Akt表达上调使MM细胞对生长抑制敏感。总的来说，我们的研究结果表明，高NEDD 4 -1水平可能是MM的潜在新治疗靶点。
E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin-proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell-expressed developmentally downregulated gene 4-1 (NEDD4-1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4-1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4-1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4-1 knockdown (KD) resulted in bortezomib resistance in MM cells in vitro and in vivo. The overexpression (OE) of NEDD4-1, but not an enzyme-dead NEDD4-1-C867S mutant, had the opposite effect. Furthermore, the overexpression of NEDD4-1 in NEDD4-1 KD cells resensitized the cells to bortezomib in an add-back rescue experiment. Mechanistically, pAkt-Ser473 levels and Akt signaling were elevated and decreased by NEDD4-1 KD and OE, respectively. NEDD4-1 ubiquitinated Akt and targeted pAkt-Ser473 for proteasomal degradation. More importantly, the NEDD4-1 KD-induced upregulation of Akt expression sensitized MM cells to growth inhibition after treatment with an Akt inhibitor. Collectively, our results suggest that high NEDD4-1 levels may be a potential new therapeutic target in MM.