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
Affiliations
Vitalyi Senyuk
Division of Hematology Oncology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
Najmeh Eskandari
Division of Hematology Oncology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
Ying Jiang
Division of Hematology Oncology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA; Departments of Anesthesiology and Pharmacology and Regenerative Medicine, University of Illinois, Chicago, IL, USA
Rebeca Garcia-Varela
Departments of Oncology and Medicine, Hematology and Oncology, and the UW Carbone Cancer Center, University of Wisconsin—Madison, Madison, WI, USA; Tecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Escuela de Ingenieria y Ciencias, Monterrey N.L., Mexico
Rachel Sundstrom
Departments of Oncology and Medicine, Hematology and Oncology, and the UW Carbone Cancer Center, University of Wisconsin—Madison, Madison, WI, USA
Luigi Leanza
Department of Biology, University of Padova, Padova, Italy
Roberta Peruzzo
Department of Biology, University of Padova, Padova, Italy
Mark Burkard
Departments of Oncology and Medicine, Hematology and Oncology, and the UW Carbone Cancer Center, University of Wisconsin—Madison, Madison, WI, USA
Richard D. Minshall
Departments of Anesthesiology and Pharmacology and Regenerative Medicine, University of Illinois, Chicago, IL, USA
Saverio Gentile
Division of Hematology Oncology, Department of Medicine, University of Illinois Chicago, Chicago, IL, USA; Corresponding author.
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.
