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

研究成果: Article査読

28 被引用数 (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.

ジャーナルBritish Journal of Cancer
出版ステータスPublished - 2012 5月 22

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究


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