PMID- 37107298
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230430
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 12
IP  - 4
DP  - 2023 Apr 13
TI  - KDELC2 Upregulates Glioblastoma Angiogenesis via Reactive Oxygen Species 
      Activation and Tumor-Associated Macrophage Proliferation.
LID - 10.3390/antiox12040923 [doi]
LID - 923
AB  - Glioblastoma is notorious for its rapid progression and neovascularization. In 
      this study, it was found that KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) 
      stimulated vasculogenic factor expression and induced human umbilical vein 
      endothelial cell (HUVEC) proliferation. The NLRP3 inflammasome and autophagy 
      activation via hypoxic inducible factor 1 alpha (HIF-1alpha) and mitochondrial 
      reactive oxygen species (ROS) production was also confirmed. The application of 
      the NLRP3 inflammasome inhibitor MCC950 and autophagy inhibitor 3-methyladenine 
      (3-MA) indicated that the above phenomenon activation correlated with an 
      endothelial overgrowth. Furthermore, KDELC2 suppression decreased the endoplasmic 
      reticulum (ER) stress factors' expression. The ER stress inhibitors, such as 
      salubrinal and GSK2606414, significantly suppressed HUVEC proliferation, 
      indicating that ER stress promotes glioblastoma vascularization. Finally, 
      shKDELC2 glioblastoma-conditioned medium (CM) stimulated TAM polarization and 
      induced THP-1 cells to transform into M1 macrophages. In contrast, THP-1 cells 
      co-cultured with compensatory overexpressed (OE)-KDELC2 glioblastoma cells 
      increased IL-10 secretion, a biomarker of M2 macrophages. HUVECs co-cultured with 
      shKDELC2 glioblastoma-polarized THP-1 cells were less proliferative, 
      demonstrating that KDELC2 promotes angiogenesis. Mito-TEMPO and MCC950 increased 
      caspase-1p20 and IL-1beta expression in THP-1 macrophages, indicating that 
      mitochondrial ROS and autophagy could also interrupt THP-1-M1 macrophage 
      polarization. In conclusion, mitochondrial ROS, ER stress, and the TAMs resulting 
      from OE-KDELC2 glioblastoma cells play important roles in upregulating 
      glioblastoma angiogenesis.
FAU - Tsai, Yu-Ling
AU  - Tsai YL
AD  - Department of Pathology, Tri-Service General Hospital, National Defense Medical 
      Center, Taipei 114, Taiwan.
FAU - Chen, Ying
AU  - Chen Y
AUID- ORCID: 0000-0001-6303-5858
AD  - Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, 
      Taiwan.
FAU - Chen, Ying-Chuan
AU  - Chen YC
AD  - Department of Physiology and Biophysics, National Defense Medical Center, Taipei 
      114, Taiwan.
FAU - Tsai, Wen-Chiuan
AU  - Tsai WC
AD  - Department of Pathology, Tri-Service General Hospital, National Defense Medical 
      Center, Taipei 114, Taiwan.
LA  - eng
GR  - MOST 109-2320-B-016-009/Ministry of Science and Technology/
GR  - TSGH-E-110229, TSGH-E-112223/Tri-Service General Hospital/
GR  - MND-MAB-D-111115/National Defense Medical Center/
PT  - Journal Article
DEP - 20230413
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC10136350
OTO - NOTNLM
OT  - ER stress
OT  - HUVEC
OT  - KDELC2
OT  - ROS
OT  - TAM
OT  - THP-1
OT  - angiogenesis
OT  - glioblastoma
OT  - macrophage differentiation
OT  - tube formation
COIS- The authors declare no conflict of interest.
EDAT- 2023/04/28 06:41
MHDA- 2023/04/28 06:42
PMCR- 2023/04/13
CRDT- 2023/04/28 01:20
PHST- 2023/03/10 00:00 [received]
PHST- 2023/04/07 00:00 [revised]
PHST- 2023/04/11 00:00 [accepted]
PHST- 2023/04/28 06:42 [medline]
PHST- 2023/04/28 06:41 [pubmed]
PHST- 2023/04/28 01:20 [entrez]
PHST- 2023/04/13 00:00 [pmc-release]
AID - antiox12040923 [pii]
AID - antioxidants-12-00923 [pii]
AID - 10.3390/antiox12040923 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2023 Apr 13;12(4):923. doi: 10.3390/antiox12040923.