PMID- 31390487
OWN - NLM
STAT- MEDLINE
DCOM- 20200214
LR  - 20240328
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 146
IP  - 7
DP  - 2020 Apr 1
TI  - The NEDD4-1 E3 ubiquitin ligase: A potential molecular target for bortezomib 
      sensitivity in multiple myeloma.
PG  - 1963-1978
LID - 10.1002/ijc.32615 [doi]
AB  - 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.
CI  - (c) 2019 The Authors. International Journal of Cancer published by John Wiley & 
      Sons Ltd on behalf of UICC.
FAU - Huang, Xi
AU  - Huang X
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Gu, Huiyao
AU  - Gu H
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Zhang, Enfan
AU  - Zhang E
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Chen, Qingxiao
AU  - Chen Q
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Cao, Wen
AU  - Cao W
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Yan, Haimeng
AU  - Yan H
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Chen, Jing
AU  - Chen J
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Yang, Li
AU  - Yang L
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Lv, Ning
AU  - Lv N
AD  - Department of Pharmacy, The First Affiliated Hospital, School of Medicine, 
      Zhejiang University, Hangzhou, China.
FAU - He, Jingsong
AU  - He J
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
FAU - Yi, Qing
AU  - Yi Q
AD  - Center for Hematologic Malignancy Research Institute, Houston Methodist, Houston, 
      TX.
FAU - Cai, Zhen
AU  - Cai Z
AUID- ORCID: 0000-0001-6026-3804
AD  - Bone Marrow Transplantation Center, Department of Hematology, The First 
      Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
AD  - Institute of Hematology, Zhejiang University, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190824
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 69G8BD63PP (Bortezomib)
RN  - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases)
RN  - EC 2.3.2.26 (Nedd4 protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
EIN - Int J Cancer. 2020 Jul 15;147(2):E4. PMID: 32445544
MH  - Animals
MH  - Bortezomib/*pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - *Drug Resistance, Neoplasm
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Male
MH  - Mice
MH  - Multiple Myeloma/drug therapy/mortality/*pathology
MH  - Nedd4 Ubiquitin Protein Ligases/genetics/*metabolism
MH  - Primary Cell Culture
MH  - Prognosis
MH  - Proteolysis
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ubiquitination
MH  - Xenograft Model Antitumor Assays
PMC - PMC7027789
OTO - NOTNLM
OT  - Akt
OT  - Bortezomib
OT  - Multiple myeloma
OT  - NEDD4-1
OT  - Ubiquitination
EDAT- 2019/08/08 06:00
MHDA- 2020/02/15 06:00
PMCR- 2020/02/18
CRDT- 2019/08/08 06:00
PHST- 2019/03/05 00:00 [received]
PHST- 2019/07/04 00:00 [revised]
PHST- 2019/07/31 00:00 [accepted]
PHST- 2019/08/08 06:00 [pubmed]
PHST- 2020/02/15 06:00 [medline]
PHST- 2019/08/08 06:00 [entrez]
PHST- 2020/02/18 00:00 [pmc-release]
AID - IJC32615 [pii]
AID - 10.1002/ijc.32615 [doi]
PST - ppublish
SO  - Int J Cancer. 2020 Apr 1;146(7):1963-1978. doi: 10.1002/ijc.32615. Epub 2019 Aug 
      24.