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Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs
Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220394/ https://www.ncbi.nlm.nih.gov/pubmed/34147842 http://dx.doi.org/10.1016/j.redox.2021.102030 |
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author | Senyuk, Vitalyi Eskandari, Najmeh Jiang, Ying Garcia-Varela, Rebeca Sundstrom, Rachel Leanza, Luigi Peruzzo, Roberta Burkard, Mark Minshall, Richard D. Gentile, Saverio |
author_facet | Senyuk, Vitalyi Eskandari, Najmeh Jiang, Ying Garcia-Varela, Rebeca Sundstrom, Rachel Leanza, Luigi Peruzzo, Roberta Burkard, Mark Minshall, Richard D. Gentile, Saverio |
author_sort | Senyuk, Vitalyi |
collection | PubMed |
description | Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive oxygen species (ROS) production and fragmentation in breast cancer cell lines and patient-derived organoids independent of breast cancer subtype. mRNA expression profiling revealed that Kv11.1 activity significantly altered expression of genes controlling the production of ROS and endoplasmic-reticulum (ER) stress. Characterization of the transcriptional signature of breast cancer cells treated with Kv11.1 potassium channel activators strikingly revealed an adaptive response to the potentially lethal augmentation of ROS by increasing Nrf2-dependent transcription of antioxidant genes. Nrf2 in this context was shown to promote survival in breast cancer, whereas knockdown of Nrf2 lead to Kv11.1-induced cell death. In conclusion, we found that the Kv11.1 channel activity promotes oxidative stress in breast cancer cells and that suppression of the Nrf2-mediated anti-oxidant survival mechanism strongly sensitized breast cancer cells to a lethal effect of pharmacological activation of Kv11.1. |
format | Online Article Text |
id | pubmed-8220394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-82203942021-06-28 Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs Senyuk, Vitalyi Eskandari, Najmeh Jiang, Ying Garcia-Varela, Rebeca Sundstrom, Rachel Leanza, Luigi Peruzzo, Roberta Burkard, Mark Minshall, Richard D. Gentile, Saverio Redox Biol Research Paper Potassium channels are important regulators of cellular homeostasis and targeting these proteins pharmacologically is unveiling important mechanisms in cancer cell biology. Here we demonstrate that pharmacological stimulation of the Kv11.1 potassium channel activity results in mitochondrial reactive oxygen species (ROS) production and fragmentation in breast cancer cell lines and patient-derived organoids independent of breast cancer subtype. mRNA expression profiling revealed that Kv11.1 activity significantly altered expression of genes controlling the production of ROS and endoplasmic-reticulum (ER) stress. Characterization of the transcriptional signature of breast cancer cells treated with Kv11.1 potassium channel activators strikingly revealed an adaptive response to the potentially lethal augmentation of ROS by increasing Nrf2-dependent transcription of antioxidant genes. Nrf2 in this context was shown to promote survival in breast cancer, whereas knockdown of Nrf2 lead to Kv11.1-induced cell death. In conclusion, we found that the Kv11.1 channel activity promotes oxidative stress in breast cancer cells and that suppression of the Nrf2-mediated anti-oxidant survival mechanism strongly sensitized breast cancer cells to a lethal effect of pharmacological activation of Kv11.1. Elsevier 2021-06-12 /pmc/articles/PMC8220394/ /pubmed/34147842 http://dx.doi.org/10.1016/j.redox.2021.102030 Text en © 2021 The Authors. Published by Elsevier B.V. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Paper Senyuk, Vitalyi Eskandari, Najmeh Jiang, Ying Garcia-Varela, Rebeca Sundstrom, Rachel Leanza, Luigi Peruzzo, Roberta Burkard, Mark Minshall, Richard D. Gentile, Saverio Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title | Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title_full | Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title_fullStr | Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title_full_unstemmed | Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title_short | Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs |
title_sort | compensatory expression of nrf2-dependent antioxidant genes is required to overcome the lethal effects of kv11.1 activation in breast cancer cells and pdos |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220394/ https://www.ncbi.nlm.nih.gov/pubmed/34147842 http://dx.doi.org/10.1016/j.redox.2021.102030 |
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