1. ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
- Author
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Jin Young Baik, Chamila C. Kadigamuwa, Zhenyu Cai, Jiong Yan, Zheng-gang Liu, Swati Choksi, Michael J. Kruhlak, Hyung-Joon Kwon, Moran Choe, Ross Lake, Delong Jiao, Mayank Tandon, and Zhaoshan Liu
- 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 - 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.
- Published
- 2021