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Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis
The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side e...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883066/ https://www.ncbi.nlm.nih.gov/pubmed/31780644 http://dx.doi.org/10.1038/s41419-019-2143-7 |
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author | Gagliardi, Mara Cotella, Diego Santoro, Claudio Corà, Davide Barlev, Nickolai A. Piacentini, Mauro Corazzari, Marco |
author_facet | Gagliardi, Mara Cotella, Diego Santoro, Claudio Corà, Davide Barlev, Nickolai A. Piacentini, Mauro Corazzari, Marco |
author_sort | Gagliardi, Mara |
collection | PubMed |
description | The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells. |
format | Online Article Text |
id | pubmed-6883066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68830662019-11-29 Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis Gagliardi, Mara Cotella, Diego Santoro, Claudio Corà, Davide Barlev, Nickolai A. Piacentini, Mauro Corazzari, Marco Cell Death Dis Article The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells. Nature Publishing Group UK 2019-11-28 /pmc/articles/PMC6883066/ /pubmed/31780644 http://dx.doi.org/10.1038/s41419-019-2143-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gagliardi, Mara Cotella, Diego Santoro, Claudio Corà, Davide Barlev, Nickolai A. Piacentini, Mauro Corazzari, Marco Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title | Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title_full | Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title_fullStr | Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title_full_unstemmed | Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title_short | Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis |
title_sort | aldo-keto reductases protect metastatic melanoma from er stress-independent ferroptosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883066/ https://www.ncbi.nlm.nih.gov/pubmed/31780644 http://dx.doi.org/10.1038/s41419-019-2143-7 |
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