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ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
- Source :
- Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
ZBP1
Science
Necroptosis
Regulator
Mice, Nude
General Physics and Astronomy
Breast Neoplasms
Biology
General Biochemistry, Genetics and Molecular Biology
Metastasis
03 medical and health sciences
RIPK1
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Mice, Knockout
Mice, Inbred BALB C
Multidisciplinary
RNA-Binding Proteins
Cancer
Neoplasms, Experimental
General Chemistry
medicine.disease
Xenograft Model Antitumor Assays
HEK293 Cells
RNAi Therapeutics
030104 developmental biology
Cytoplasm
Receptor-Interacting Protein Serine-Threonine Kinases
030220 oncology & carcinogenesis
MCF-7 Cells
Cancer research
Tumor necrosis factor alpha
Subjects
Details
- ISSN :
- 20411723
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....c8913a4fcd50014ee8b165480f67e5e7