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Cholinergic Ligand–dependent Modulation of Oxidative Phosphorylation Coupling in Digitonin-permeabilized BE(2)-C Neuroblastoma Cells
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Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase

H Hiyoshi1, S Abdelhady, L Segerström

  • 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.

British Journal of Cancer
|April 26, 2012
PubMed
Abstract

Insights

Ouabain, a cardiac glycoside, induces reversible cell cycle arrest in neuroblastoma by targeting the Na,K-ATPase. This discovery suggests ouabain as a potential therapy to suppress tumor growth and enhance combination treatments.

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Cellular quiescence is a reversible state of proliferation arrest.
  • Ouabain, an endogenous cardiac glycoside, binds to Na,K-ATPase and influences cell growth via signaling pathways.

Purpose of the Study:

  • Investigate the role of ouabain/Na,K-ATPase in neuroblastoma growth.
  • Determine ouabain's potential as a therapeutic agent.

Main Methods:

  • Utilized xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology.
  • Administered ouabain treatments to neuroblastoma models.

Main Results:

  • Ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma.
  • Tumor growth reduced by over 50% in ouabain-fed mice.
  • Ouabain triggered S-G2 phase arrest, activated DNA-damage response (γH2AX), increased p21(Waf1/Cip1), and upregulated HES1, leading to G0 arrest. Cells resumed proliferation without DNA damage upon ouabain removal.

Conclusions:

  • Ouabain/Na,K-ATPase is a novel regulator of quiescence in neuroblastoma.
  • Ouabain shows potential for chemotherapy to suppress tumor growth.
  • Ouabain can arrest cells, potentially increasing the therapeutic index in combination therapies.

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