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

Le Ba Nam1, Young-Sam Keum1

  • 1College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, Goyang, Korea.

Free Radical Research
|March 3, 2020
PubMed

Insights

This study reveals that inhibiting Na+/K+-ATPase downregulates NRF2, a key protein in cancer cell adaptation. This pathway, involving Ca2+, CSK1, and Src, offers a new target for NRF2 inhibitor development in cancer therapy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Tumors utilize high NRF2 levels to manage oxidative stress, making NRF2 inhibition a promising chemotherapeutic strategy.
  • Na+/K+-ATPase activity is crucial for cellular homeostasis and has been implicated in various diseases.

Purpose of the Study:

  • To investigate the regulatory role of Na+/K+-ATPase in NRF2 expression in A549 lung cancer cells.
  • To identify the molecular mechanisms linking Na+/K+-ATPase activity to NRF2 regulation.
  • To explore the potential of targeting the Na+/K+-ATPase-CSK1-Src axis for NRF2-targeted cancer therapy.

Main Methods:

  • Utilized convallatoxin and siRNAs to suppress Na+/K+-ATPase function in A549 cells.
  • Assessed NRF2 levels, intracellular reactive oxygen species (ROS) generation, and cisplatin-induced apoptosis and autophagy.
  • Investigated the involvement of Ca2+, CSK1, and Src phosphorylation in the regulatory pathway.

Main Results:

  • Suppression of Na+/K+-ATPase led to NRF2 downregulation in A549 cells.
  • This effect was mediated by Ca2+-dependent induction of CSK1 and subsequent Src phosphorylation at Tyr 527.
  • Knocking down Na+/K+-ATPase subunits enhanced cisplatin-induced ROS production, apoptosis, and autophagy.

Conclusions:

  • Na+/K+-ATPase plays a significant role in regulating NRF2 expression in lung cancer cells.
  • The identified signaling axis (Na+/K+-ATPase-CSK1-Src) represents a novel therapeutic target for developing NRF2 inhibitors.
  • Targeting this pathway could potentiate the efficacy of chemotherapeutic agents like cisplatin.
Keywords:
Antioxidant response element (ARE)C-terminal kinase 1 (CSK1)NF-E2-related factor 2 (NRF2)Na+/K+-translocating adenosine triphosphatase (Na+/K+-ATPase)Reactive oxygen species (ROS)

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