ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer.
Animals
Breast Neoplasms
/ genetics
Cell Line, Tumor
HEK293 Cells
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Necroptosis
/ genetics
Neoplasms, Experimental
/ genetics
RNA-Binding Proteins
/ genetics
RNAi Therapeutics
/ methods
Receptor-Interacting Protein Serine-Threonine Kinases
/ genetics
Xenograft Model Antitumor Assays
/ methods
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 05 2021
11 05 2021
Historique:
received:
03
04
2020
accepted:
12
04
2021
entrez:
12
5
2021
pubmed:
13
5
2021
medline:
2
6
2021
Statut:
epublish
Résumé
Tumor necrosis happens commonly in advanced solid tumors. We reported that necroptosis plays a major role in tumor necrosis. Although several key necroptosis regulators including receptor interacting protein kinase 1 (RIPK1) have been identified, the regulation of tumor necroptosis during tumor development remains elusive. Here, we report that Z-DNA-binding protein 1 (ZBP1), not RIPK1, mediates tumor necroptosis during tumor development in preclinical cancer models. We found that ZBP1 expression is dramatically elevated in necrotic tumors. Importantly, ZBP1, not RIPK1, deletion blocks tumor necroptosis during tumor development and inhibits metastasis. We showed that glucose deprivation triggers ZBP1-depedent necroptosis in tumor cells. Glucose deprivation causes mitochondrial DNA (mtDNA) release to the cytoplasm and the binding of mtDNA to ZBP1 to activate MLKL in a BCL-2 family protein, NOXA-dependent manner. Therefore, our study reveals ZBP1 as the key regulator of tumor necroptosis and provides a potential drug target for controlling tumor metastasis.
Identifiants
pubmed: 33976222
doi: 10.1038/s41467-021-23004-3
pii: 10.1038/s41467-021-23004-3
pmc: PMC8113527
doi:
Substances chimiques
RNA-Binding Proteins
0
ZBP1 protein, human
0
Zbp1 protein, mouse
0
RIPK1 protein, human
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
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