PMID- 37083684
OWN - NLM
STAT- MEDLINE
DCOM- 20231107
LR  - 20231107
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 7
IP  - 19
DP  - 2023 Oct 10
TI  - TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival 
      autophagy.
PG  - 5752-5770
LID - 10.1182/bloodadvances.2022008241 [doi]
AB  - Bortezomib (bort) is an effective therapeutic agent for patients with multiple 
      myeloma (MM); however, most patients develop drug resistance. Autophagy, a highly 
      conserved process that recycles cytosol or entire organelles via lysosomal 
      activity, is essential for the survival, homeostasis, and drug resistance in MM. 
      Growing evidence has highlighted that E3 ligase tripartite motif-containing 
      protein 21 (TRIM21) not only interacts with multiple autophagy regulators but 
      also participates in drug resistance in various cancers. However, to date, the 
      direct substrates and additional roles of TRIM21 in MM remain unexplored. In this 
      study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. 
      TRIM21 knockdown (KD) made MM cells more resistant to bort, whereas TRIM21 
      overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and 
      phosphoproteomic studies of TRIM21 KD MM cells showed that bort resistance was 
      associated with increased oxidative stress and elevated prosurvival autophagy. 
      Our results showed that TRIM21 KD MM cell lines induced prosurvival autophagy 
      after bort treatment, suppressing autophagy by 3-methyladenine treatment or by 
      the short hairpin RNA of autophagy-related gene 5 (ATG5)-restored-bort 
      sensitivity. Indeed, ATG5 expression was increased and decreased by TRIM21 KD and 
      OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 
      for proteasomal degradation. Importantly, we confirmed that TRIM21 could 
      potentiate the antimyeloma effect of bort through in vitro and in vivo 
      experiments. Overall, our findings define the key role of TRIM21 in MM bort 
      resistance and provide a foundation for a novel targeted therapeutic approach.
CI  - (c) 2023 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Chen, Jing
AU  - Chen J
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Cao, Wen
AU  - Cao W
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Huang, Xi
AU  - Huang X
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Chen, Qingxiao
AU  - Chen Q
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Ye, Shuting
AU  - Ye S
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Qu, Jianwei
AU  - Qu J
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Liu, Yang
AU  - Liu Y
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Guo, Xing
AU  - Guo X
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Yao, Shunnan
AU  - Yao S
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Zhang, Enfan
AU  - Zhang E
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - He, Jingsong
AU  - He J
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Li, Anqi
AU  - Li A
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Yang, Li
AU  - Yang L
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
FAU - Cai, Zhen
AU  - Cai Z
AUID- ORCID: 0000-0001-6026-3804
AD  - Bone Marrow Transplantation Center, The First Affiliated Hospital, School of 
      Medicine, Zhejiang University, Hangzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 69G8BD63PP (Bortezomib)
RN  - 0 (Transcription Factors)
RN  - 0 (SS-A antigen)
RN  - 0 (Ribonucleoproteins)
SB  - IM
MH  - Humans
MH  - Autophagy
MH  - Bortezomib/pharmacology/therapeutic use
MH  - *Multiple Myeloma/drug therapy/genetics
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Proteomics
MH  - Transcription Factors
MH  - *Ribonucleoproteins/metabolism
PMC - PMC10561007
COIS- Conflict-of-interest disclosure: The anthors declare no competing financial 
      interests.
EDAT- 2023/04/21 18:43
MHDA- 2023/10/23 12:45
PMCR- 2023/04/24
CRDT- 2023/04/21 14:46
PHST- 2023/04/09 00:00 [accepted]
PHST- 2022/06/01 00:00 [received]
PHST- 2023/10/23 12:45 [medline]
PHST- 2023/04/21 18:43 [pubmed]
PHST- 2023/04/21 14:46 [entrez]
PHST- 2023/04/24 00:00 [pmc-release]
AID - 495419 [pii]
AID - 10.1182/bloodadvances.2022008241 [doi]
PST - ppublish
SO  - Blood Adv. 2023 Oct 10;7(19):5752-5770. doi: 10.1182/bloodadvances.2022008241.