Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs

Vitalyi Senyuk; Najmeh Eskandari; Ying Jiang; Rebeca Garcia-Varela; Rachel Sundstrom; Luigi Leanza; Roberta Peruzzo; Mark Burkard; Richard D. Minshall; Saverio Gentile

doi:10.1016/j.redox.2021.102030

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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

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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

Vitalyi Senyuk, Najmeh Eskandari, Ying Jiang, Rebeca Garcia-Varela, Rachel Sundstrom, Luigi Leanza, Roberta Peruzzo, Mark Burkard, Richard D. Minshall and Saverio Gentile

Redox biology, Vol.45, pp.102030-102030

09/01/2021

DOI: 10.1016/j.redox.2021.102030

PMCID: PMC8220394

PMID: 34147842

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Abstract

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.

Cancer cell survival

Mitochondria

NRF2

Potassium channels

Details

Title: Subtitle: Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs
Creators: Vitalyi Senyuk - University of Illinois Urbana-Champaign
Najmeh Eskandari - University of Illinois Urbana-Champaign
Ying Jiang - University of Illinois Urbana-Champaign
Rebeca Garcia-Varela - University of Wisconsin Carbone Cancer Center
Rachel Sundstrom - University of Wisconsin Carbone Cancer Center
Luigi Leanza - Department of Biology, University of Padova, Padova, Italy
Roberta Peruzzo - Department of Biology, University of Padova, Padova, Italy
Mark Burkard - University of Wisconsin Carbone Cancer Center
Richard D. Minshall - University of Illinois Urbana-Champaign
Saverio Gentile - University of Illinois Urbana-Champaign
Resource Type: Journal article
Publication Details: Redox biology, Vol.45, pp.102030-102030
DOI: 10.1016/j.redox.2021.102030
PMID: 34147842
PMCID: PMC8220394
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier B.V
Language: English
Date published: 09/01/2021
Academic Unit: Internal Medicine
Record Identifier: 9984700653402771

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