ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
Jin Young Baik1, Zhaoshan Liu1, Delong Jiao1
1National Cancer Institute; National Institutes of Health, Laboratory of Immune Cell Biology, Bethesda, MD, USA.
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.
Insights
Z-DNA-binding protein 1 (ZBP1) drives tumor necroptosis and metastasis in preclinical cancer models. Blocking ZBP1, not RIPK1, inhibits tumor necroptosis and tumor spread, offering a potential therapeutic target.
Area of Science:
- Oncology
- Cellular Biology
- Immunology
Background:
- Necroptosis, a programmed form of necrosis, is prevalent in advanced solid tumors.
- While receptor interacting protein kinase 1 (RIPK1) is a known necroptosis regulator, its role in tumor development is unclear.
- Understanding tumor necroptosis regulation is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the key regulators of tumor necroptosis during tumor development.
- To determine the role of Z-DNA-binding protein 1 (ZBP1) in mediating tumor necroptosis.
- To explore ZBP1 as a potential therapeutic target for inhibiting tumor metastasis.
Main Methods:
- Utilized preclinical cancer models to study tumor necroptosis.
- Assessed the expression levels of ZBP1 in necrotic tumors.
- Investigated the effect of ZBP1 deletion on tumor necroptosis and metastasis.
- Examined the molecular mechanisms of ZBP1 activation, including glucose deprivation and mitochondrial DNA (mtDNA) release.
Main Results:
- ZBP1 expression is significantly elevated in necrotic tumors.
- Deletion of ZBP1, but not RIPK1, effectively blocks tumor necroptosis and inhibits metastasis.
- Glucose deprivation induces ZBP1-dependent necroptosis in tumor cells.
- Activated ZBP1 binds to released mtDNA, leading to MLKL activation in a NOXA-dependent manner.
Conclusions:
- Z-DNA-binding protein 1 (ZBP1) is the primary mediator of tumor necroptosis during tumor development, independent of RIPK1.
- ZBP1 activation is triggered by glucose deprivation and subsequent mtDNA release.
- Targeting ZBP1 presents a promising therapeutic strategy for controlling tumor necroptosis and inhibiting cancer metastasis.
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