Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis

Hsin Chih Chen, Han Hsuan Tang, Wei Hsiang Hsu, Shan Ying Wu, Wen Hsing Cheng, Bao Yuan Wang, Chun Li Su

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting ferritin via autophagy (ferritinophagy) to induce ferroptosis, an iron-and re-active oxygen species (ROS)-dependent cell death, provides novel strategies for cancer therapy. Using a ferroptosis-specific inhibitor and iron chelator, the vulnerability of triple-negative breast cancer (TNBC) MDA-MB-231 cells to ferroptosis was identified and compared to that of luminal A MCF-7 cells. Saponin formosanin C (FC) was revealed as a potent ferroptosis inducer characterized by superior induction in cytosolic and lipid ROS formation as well as GPX4 depletion in MDA-MB-231 cells. The FC-induced ferroptosis was paralleled by downregulation of ferroportin and xCT expressions. Immunoprecipitation and electron microscopy demonstrated the involve-ment of ferritinophagy in FC-treated MDA-MB-231 cells. The association of FC with ferroptosis was strengthened by the results that observed an enriched pathway with differentially expressed genes from FC-treated cells. FC sensitized cisplatin-induced ferroptosis in MDA-MB-231 cells. Through integrated analysis of differentially expressed genes and pathways using the METABRIC patients’ database, we confirmed that autophagy and ferroptosis were discrepant between TNBC and luminal A and that TNBC was hypersensitive to ferroptosis. Our data suggest a therapeutic strategy by ferroptosis against TNBC, an aggressive subtype with a poor prognosis.

Original languageEnglish
Article number298
JournalAntioxidants
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 2022

Keywords

  • Breast cancer
  • Ferritinophagy
  • Ferroptosis potential index
  • Formosanin C
  • Gene database

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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