The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma. Issue 7 (24th August 2019)

• Record Type: Journal Article
• Authors: Huang, Xi; Gu, Huiyao; Zhang, Enfan; Chen, Qingxiao; Cao, Wen; Yan, Haimeng; Chen, Jing; Yang, Li; Lv, Ning; He, Jingsong; Yi, Qing; Cai, Zhen
• Is Part Of: International journal of cancer. Volume 146:Issue 7(2020)
• Page Start: 1963
• Page End: 1978
• Publication Date: 2019-08-24
• Subjects: NEDD4‐1 -- Akt -- Bortezomib -- Ubiquitination -- Multiple myeloma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32615
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : 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. Abstract : What's new? While multiple myeloma (MM) remains an incurable disease, therapeutic advances have greatly improved its clinical management. Among the agents most effective against MM is the proteasome inhibitor bortezomib, though many patients eventually develop drug resistance. Here, decreased expression of the tumor suppressor NEDD4‐1 was found to serve a key role in modulating MM sensitivity to bortezomib. Reduced NEDD4‐1 expression was associated with increased PTEN/PI3K/Akt signaling and tumor growth. Experiments showed that NEDD4‐1 normally binds directly to Akt, enhancing its ubiquitination and thereby exerting anti‐MM effects. The data warrant further investigation of NEDD4‐1 reactivation as a novel therapeutic strategy for MM.