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

International Journal of Cancer. Journal International Du Cancer
Xi HuangZhen Cai

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 expr...Continue Reading

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Citations

Dec 4, 2019·Cell Death & Disease·Xi HuangZhen Cai
Nov 10, 2020·Archives of Pharmacal Research·Jinyoung ParkEun Joo Song
May 4, 2021·Frontiers in Pharmacology·Yuanqi LiuChunfang Zhang

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Methods Mentioned

BETA
ELISA
ubiquitination
flow cytometry
electrophoresis
pulldown
immunoprecipitation
xenograft
biopsy
confocal
biopsies

Software Mentioned

pro plus
Quant center
FlowJo X
Image Lab
GraphPad Prism
Image
ModFit
Prism
GraphPad

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