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Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma
Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibriu...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283515/ https://www.ncbi.nlm.nih.gov/pubmed/32416440 http://dx.doi.org/10.1016/j.tranon.2020.100785 |
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author | Lippmann, Jana Petri, Kathrin Fulda, Simone Liese, Juliane |
author_facet | Lippmann, Jana Petri, Kathrin Fulda, Simone Liese, Juliane |
author_sort | Lippmann, Jana |
collection | PubMed |
description | Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC. In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC. |
format | Online Article Text |
id | pubmed-7283515 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72835152020-06-14 Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma Lippmann, Jana Petri, Kathrin Fulda, Simone Liese, Juliane Transl Oncol Original article Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC. In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC. Neoplasia Press 2020-05-13 /pmc/articles/PMC7283515/ /pubmed/32416440 http://dx.doi.org/10.1016/j.tranon.2020.100785 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Lippmann, Jana Petri, Kathrin Fulda, Simone Liese, Juliane Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title | Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title_full | Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title_fullStr | Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title_full_unstemmed | Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title_short | Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma |
title_sort | redox modulation and induction of ferroptosis as a new therapeutic strategy in hepatocellular carcinoma |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283515/ https://www.ncbi.nlm.nih.gov/pubmed/32416440 http://dx.doi.org/10.1016/j.tranon.2020.100785 |
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