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

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22 Citations (Scopus)

Abstract

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
Volume106
Issue number11
DOIs
Publication statusPublished - 2012 May 22

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hiyoshi, H., Abdelhady, S., Segerström, L., Sveinbjörnsson, B., Nuriya, M., Lundgren, T. K., Desfrere, L., Miyakawa, A., Yasui, M., Kogner, P., Johnsen, J. I., Andäng, M., & Uhlén, P. (2012). Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. British Journal of Cancer, 106(11), 1807-1815. https://doi.org/10.1038/bjc.2012.159