Compensatory expression of NRF2-dependent antioxidant genes is required to overcome the lethal effects of Kv11.1 activation in breast cancer cells and PDOs
| Autor: | Ying Jiang, Mark E. Burkard, Roberta Peruzzo, Rachel Sundstrom, Najmeh Eskandari, Vitalyi Senyuk, Rebeca García-Varela, Richard D. Minshall, Saverio Gentile, Luigi Leanza |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Medicine (General) NF-E2-Related Factor 2 Cancer cell survival QH301-705.5 Clinical Biochemistry Cellular homeostasis Breast Neoplasms Mitochondrion Biochemistry Antioxidants Mitochondria NRF2 Potassium channels Endoplasmic Reticulum Stress Female Humans Reactive Oxygen Species Breast cancer R5-920 medicine Biology (General) Gene knockdown Chemistry Organic Chemistry medicine.disease Potassium channel Potassium channel activity Cancer cell Cancer research Research Paper |
| Zdroj: | Redox Biology, Vol 45, Iss, Pp 102030-(2021) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|