ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer

Nat Commun. 2021 May 11;12(1):2666. doi: 10.1038/s41467-021-23004-3.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Necroptosis / genetics*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • RNAi Therapeutics / methods
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • RNA-Binding Proteins
  • ZBP1 protein, human
  • Zbp1 protein, mouse
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases