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 language | English |
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Article number | 298 |
Journal | Antioxidants |
Volume | 11 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2022 Feb |
Keywords
- Breast cancer
- Ferritinophagy
- Ferroptosis potential index
- Formosanin C
- Gene database
ASJC Scopus subject areas
- Food Science
- Molecular Biology
- Physiology
- Biochemistry
- Clinical Biochemistry
- Cell Biology