RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

Cell Death Differ. 2020 Jul;27(7):2234-2247. doi: 10.1038/s41418-020-0499-y. Epub 2020 Jan 27.

Abstract

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically reexpressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo necroptosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Proliferation / drug effects
  • Cystine / metabolism*
  • Epigenesis, Genetic / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / pathology*
  • Mitosis / drug effects
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology*
  • Piperazines / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Transcriptome / genetics
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Piperazines
  • Tumor Suppressor Protein p53
  • Wwtr1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • erastin
  • Cystine
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse