Regulation of NRF2 by Na⁺/K⁺-ATPase: implication of tyrosine phosphorylation of Src

Abstract

Tumors adapt well to the imbalanced redox status created by rapid growth and limited nutrient availability because they highly express high levels of NRF2 to counteract oxidative stress. Therefore, inhibition of NRF2 is currently considered a feasible strategy for development of chemotherapeutic agents. In the present study, we identified that Na⁺/K⁺-ATPase regulates NRF2 in A549 cells. Suppression of Na⁺/K⁺-ATPase by convallatoxin or siRNAs downregulates NRF2 in A549 cells, and this event is mediated by Ca²⁺-dependent induction of CSK1 and subsequent phosphorylation of SRC at Tyr 527. Consistent with this finding, knocking down the α1 or β1 subunit of Na⁺/K⁺-ATPase promotes the generation of intracellular ROS by cisplatin and potentiates cisplatin-induced apoptosis and autophagy in A549 cells. Our study reveals that the signaling axis composed of Na⁺/K⁺-ATPase, CSK1, and tyrosine phosphorylation of Src could be a useful target for development of NRF2 inhibitors.

Keywords:

• Antioxidant response element (ARE)
• Na+/K+-translocating adenosine triphosphatase (Na+/K+-ATPase)
• NF-E2-related factor 2 (NRF2)
• C-terminal kinase 1 (CSK1)
• Reactive oxygen species (ROS)

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF 2018R1A5A2023127) and the Gyeonggi Regional Research Center Program of Gyeonggi Province (GRRC 2017-B01).