Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis
Targeting ferritin via autophagy (ferritinophagy) to induce ferroptosis, an iron- and reactive 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)...
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MDPI AG
2022-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/2/298 |
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| author | Hsin-Chih Chen Han-Hsuan Tang Wei-Hsiang Hsu Shan-Ying Wu Wen-Hsing Cheng Bao-Yuan Wang Chun-Li Su |
| author_facet | Hsin-Chih Chen Han-Hsuan Tang Wei-Hsiang Hsu Shan-Ying Wu Wen-Hsing Cheng Bao-Yuan Wang Chun-Li Su |
| author_sort | Hsin-Chih Chen |
| collection | DOAJ |
| description | Targeting ferritin via autophagy (ferritinophagy) to induce ferroptosis, an iron- and reactive 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 involvement 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. |
| first_indexed | 2024-03-09T22:44:09Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T22:44:09Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj.art-08e6a95a30ee4c189396d2124d7f80782023-11-23T18:31:34ZengMDPI AGAntioxidants2076-39212022-01-0111229810.3390/antiox11020298Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced FerroptosisHsin-Chih Chen0Han-Hsuan Tang1Wei-Hsiang Hsu2Shan-Ying Wu3Wen-Hsing Cheng4Bao-Yuan Wang5Chun-Li Su6Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, TaiwanGraduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei 116, TaiwanGraduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei 116, TaiwanGraduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei 116, TaiwanDepartment of Food Science, Nutrition, and Health Promotion, Mississippi State University, Starkville, MS 39762, USAGraduate Program of Nutrition Science, School of Life Science, National Taiwan Normal University, Taipei 116, TaiwanDepartment of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, TaiwanTargeting ferritin via autophagy (ferritinophagy) to induce ferroptosis, an iron- and reactive 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 involvement 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.https://www.mdpi.com/2076-3921/11/2/298formosanin Cbreast cancerferroptosis potential indexferritinophagygene database |
| spellingShingle | Hsin-Chih Chen Han-Hsuan Tang Wei-Hsiang Hsu Shan-Ying Wu Wen-Hsing Cheng Bao-Yuan Wang Chun-Li Su Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis Antioxidants formosanin C breast cancer ferroptosis potential index ferritinophagy gene database |
| title | Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis |
| title_full | Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis |
| title_fullStr | Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis |
| title_full_unstemmed | Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis |
| title_short | Vulnerability of Triple-Negative Breast Cancer to Saponin Formosanin C-Induced Ferroptosis |
| title_sort | vulnerability of triple negative breast cancer to saponin formosanin c induced ferroptosis |
| topic | formosanin C breast cancer ferroptosis potential index ferritinophagy gene database |
| url | https://www.mdpi.com/2076-3921/11/2/298 |
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