ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer

Jin Young Baik, Zhaoshan Liu, Delong Jiao, Hyung-Joon Kwon, Jiong Yan, Chamila Kadigamuwa, Moran Choe, Ross Lake, Michael Kruhlak, Mayank Tandon, Zhenyu Cai, Swati Choksi and Zheng-gang Liu ()
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Jin Young Baik: Laboratory of Immune Cell Biology
Zhaoshan Liu: Laboratory of Immune Cell Biology
Delong Jiao: Laboratory of Immune Cell Biology
Hyung-Joon Kwon: Laboratory of Immune Cell Biology
Jiong Yan: Laboratory of Immune Cell Biology
Chamila Kadigamuwa: Laboratory of Immune Cell Biology
Moran Choe: Laboratory of Immune Cell Biology
Ross Lake: Laboratory of Genitourinary Cancer Pathogenesis
Michael Kruhlak: Laboratory of Cancer Biology and Genetics
Mayank Tandon: Collaborative Bioinformatics Resource
Zhenyu Cai: Tongji University
Swati Choksi: Laboratory of Immune Cell Biology
Zheng-gang Liu: Laboratory of Immune Cell Biology

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23004-3

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