The NEDD4‐1 E3 ubiquitin ligase: A potential molecular target for bortezomib sensitivity in multiple myeloma

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.

RETRACTED: MicroRNA-27 Inhibits Autophagy and Promotes Proliferation of Multiple Myeloma Cells by Targeting the NEDD4/Notch1 Axis

“…In this study, we further proceeded to clarify the regulatory mechanism of miR-27 through targeting the NEDD4/Notch1 axis in MM cells. It is noted that E3 ubiquitin ligase NEDD4 downregulation has been associated with unfavorable prognosis of MM patients, due to the contribution to drug resistance ( 22 ). Emerging studies documented that NEDD4 exerted a promotive regulation of autophagy through different mechanisms in different types of cells.…”

“…A wide array of studies have revealed cytogenetic and epigenetic changes in MM cells, which influence cellular proliferation, apoptosis, autophagy, and metastasis through different mechanisms, including the regulatory effects of microRNAs (miRNAs) on the progression of MM (5). miRNAs are small single-stranded RNAs (19)(20)(21)(22) nucleotide in length), which participate in various malignant biological processes of MM (6). Different effects have been identified for specific miRNAs on MM cells, including pro-tumoral and antitumoral properties.…”

Environmental control of Pub1 (NEDD4 family E3 ligase) inS. pombeis regulated by TORC2 and Gsk3

“…Our observation suggests that reduced GSK3 activity as a result of insulin signaling may decrease NEDD4 levels and thus put a brake on insulin and growth factor signalling through a negative feedback loop. However, in human cells NEDD4 can directly bind to and ubiquitinate AKT which is prior phosphorylated on pS473, to degrade active AKT 52 . Thus, decreased GSK3 activity and therefore reduced NEDD4 levels would increase active AKT pS473, providing a positive feedback for insulin and growth factor signalling and glucose uptake to counteract the negative feedback and establish a steady state.…”

The emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance

“…In addition, NEDD4 is highly expressed in erlotinib-resistant NSCLC cells and cisplatinresistant nasopharyngeal carcinoma cells [41] . Nonetheless, upregulation of NEDD4 resensitized multiple myeloma cells to bortezomib treatment via ubiquitination of Akt and degradation of pAkt-Ser473, while downregulation of NEDD4 resulted in bortezomib resistance in multiple myeloma cells [42] . What's more, Akkaya et al [43] also demonstrated NEDD4 as a ubiquitin ligase for ATP binding cassette subfamily B member 1, which is a multidrug resistance pump that mediates drug resistance, indicating that NEDD4 directly participates in drug resistance.…”