Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase

H. Hiyoshi, S. Abdelhady, L. Segerström, B. Sveinbjörnsson, M. Nuriya, T. K. Lundgren, L. Desfrere, A. Miyakawa, M. Yasui, P. Kogner, J. I. Johnsen, M. Andäng, P. Uhlén

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


Background: Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways. Methods: To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies. Results: The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune-deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker γH2AX, increased the cell cycle regulator p21 Waf1/Cip1 and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed. Conclusion: These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies.

Original languageEnglish
Pages (from-to)1807-1815
Number of pages9
JournalBritish Journal of Cancer
Issue number11
Publication statusPublished - 2012 May 22


  • Na,K-ATPase
  • neuroblastoma
  • ouabain
  • quiescence
  • γH2AX

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase'. Together they form a unique fingerprint.

Cite this