PMID- 33416146
OWN - NLM
STAT- MEDLINE
DCOM- 20210712
LR  - 20210712
IS  - 1791-244X (Electronic)
IS  - 1107-3756 (Print)
IS  - 1107-3756 (Linking)
VI  - 47
IP  - 2
DP  - 2021 Feb
TI  - Regulatory role of DEPTOR‑mediated cellular autophagy and mitochondrial reactive 
      oxygen species in angiogenesis in multiple myeloma.
PG  - 643-658
LID - 10.3892/ijmm.2020.4831 [doi]
AB  - DEPTOR, an inhibitor of mammalian target of rapamycin (mTOR), is essential for 
      the survival of multiple myeloma (MM) cells. The expression level of DEPTOR is 
      closely related to the prognosis of patients with MM treated with the 
      antiangiogenic agent thalidomide; however, its role in the regulation of 
      angiogenesis has not yet been elucidated. In the present study, the expression 
      levels of DEPTOR and vascular endothelial growth factor (VEGF), and the 
      microvessel density (MVD) of bone marrow (BM) from patients with MM assessed. 
      DEPTORoverexpression plasmid or CRISPR‑associated protein 9 (Cas9) and single 
      guided RNAs (sgRNAs) were used to modulate DEPTOR expression. The DEPTOR‑mediated 
      angiogenic effects were assessed using a tube formation assay of human umbilical 
      vein endothelial cells (HUVECs) cultured in the collected conditioned medium from 
      MM cell lines with different expression levels of DEPTOR. It was found that the 
      expression level of DEPTOR negatively correlated with the VEGF level and BM MVD 
      in MM. Autophagic activity was regulated by DEPTOR expression, but was not 
      related to thalidomide‑binding protein CRBN, which is required for thalidomide to 
      play an anti‑tumor and antiangiogenic role in MM cells. The disruption of DEPTOR 
      protein decreased cellular autophagy, increased VEGF expression in MM cells, and 
      inhibited the tube formation of HUVECs, while a high expression of DEPTOR exerted 
      the opposite effect. Moreover, targeting DEPTOR also resulted in the production 
      of mitochondrial reactive oxygen species (mtROS), the phosphorylation of nuclear 
      factor‑kappaB (NF‑kappaB) and an increase in interleukin 6 (IL‑6) secretion. Of note, 
      these effects are fully abrogated by treatment with autophagy activator (SMER28) 
      or mitochondrial‑specific antioxidant (Mito‑TEMPO). Taken together, the present 
      study demonstrates the role of DEPTOR in the regulation of autophagy/mtROS and 
      subsequent angiogenesis. The results provide a novel mechanism for the further 
      understanding of the therapeutic effects of thalidomide on MM.
FAU - Wang, Jizhen
AU  - Wang J
AD  - Department of Hematology, The First Affiliated Hospital of Fujian Medical 
      University, Fuzhou, Fujian 350005, P.R. China.
FAU - Chen, Junmin
AU  - Chen J
AD  - Department of Hematology, The First Affiliated Hospital of Fujian Medical 
      University, Fuzhou, Fujian 350005, P.R. China.
FAU - Qiu, Dongbiao
AU  - Qiu D
AD  - Department of Blood Transfusion, The First Affiliated Hospital of Fujian Medical 
      University, Fuzhou, Fujian 350005, P.R. China.
FAU - Zeng, Zhiyong
AU  - Zeng Z
AD  - Department of Hematology, The First Affiliated Hospital of Fujian Medical 
      University, Fuzhou, Fujian 350005, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20201224
PL  - Greece
TA  - Int J Mol Med
JT  - International journal of molecular medicine
JID - 9810955
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.1.1 (DEPTOR protein, human)
SB  - IM
MH  - *Autophagy
MH  - Databases, Nucleic Acid
MH  - Female
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics/*metabolism
MH  - Male
MH  - Mitochondria/genetics/*metabolism
MH  - Multiple Myeloma/*blood supply/genetics/*metabolism/pathology
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Neovascularization, Pathologic/genetics/*metabolism/pathology
MH  - Reactive Oxygen Species/*metabolism
PMC - PMC7797453
OTO - NOTNLM
OT  - multiple myeloma
OT  - DEPTOR
OT  - autophagy
OT  - mitochondrial reactive oxygen species
OT  - angiogenesis
EDAT- 2021/01/09 06:00
MHDA- 2021/07/13 06:00
PMCR- 2020/12/24
CRDT- 2021/01/08 08:37
PHST- 2020/03/27 00:00 [received]
PHST- 2020/11/25 00:00 [accepted]
PHST- 2021/01/09 06:00 [pubmed]
PHST- 2021/07/13 06:00 [medline]
PHST- 2021/01/08 08:37 [entrez]
PHST- 2020/12/24 00:00 [pmc-release]
AID - ijmm-47-02-0643 [pii]
AID - 10.3892/ijmm.2020.4831 [doi]
PST - ppublish
SO  - Int J Mol Med. 2021 Feb;47(2):643-658. doi: 10.3892/ijmm.2020.4831. Epub 2020 Dec 
      24.