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

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

Research output: Contribution to journalArticle

21 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

Fingerprint

Ouabain
Neuroblastoma
Growth
DNA Damage
Cyclin-Dependent Kinase Inhibitor p21
Sodium-Potassium-Exchanging ATPase
Cardiac Glycosides
Comet Assay
sodium-translocating ATPase
G2 Phase
Electrophysiology
S Phase
Heterografts
Real-Time Polymerase Chain Reaction
Neoplasms
Cell Cycle
Flow Cytometry
Transcription Factors
Therapeutics
Ligands

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hiyoshi, H., Abdelhady, S., Segerström, L., Sveinbjörnsson, B., Nuriya, M., Lundgren, T. K., ... 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

Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. / Hiyoshi, H.; Abdelhady, S.; Segerström, L.; Sveinbjörnsson, B.; Nuriya, Mutsuo; Lundgren, T. K.; Desfrere, L.; Miyakawa, A.; Yasui, Masato; Kogner, P.; Johnsen, J. I.; Andäng, M.; Uhlén, P.

In: British Journal of Cancer, Vol. 106, No. 11, 22.05.2012, p. 1807-1815.

Research output: Contribution to journalArticle

Hiyoshi, H, Abdelhady, S, Segerström, L, Sveinbjörnsson, B, Nuriya, M, Lundgren, TK, Desfrere, L, Miyakawa, A, Yasui, M, Kogner, P, Johnsen, JI, Andäng, M & Uhlén, P 2012, 'Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase', British Journal of Cancer, vol. 106, no. 11, pp. 1807-1815. https://doi.org/10.1038/bjc.2012.159
Hiyoshi H, Abdelhady S, Segerström L, Sveinbjörnsson B, Nuriya M, Lundgren TK et al. Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. British Journal of Cancer. 2012 May 22;106(11):1807-1815. https://doi.org/10.1038/bjc.2012.159
Hiyoshi, H. ; Abdelhady, S. ; Segerström, L. ; Sveinbjörnsson, B. ; Nuriya, Mutsuo ; Lundgren, T. K. ; Desfrere, L. ; Miyakawa, A. ; Yasui, Masato ; Kogner, P. ; Johnsen, J. I. ; Andäng, M. ; Uhlén, P. / Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. In: British Journal of Cancer. 2012 ; Vol. 106, No. 11. pp. 1807-1815.
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AU - Nuriya, Mutsuo

AU - Lundgren, T. K.

AU - Desfrere, L.

AU - Miyakawa, A.

AU - Yasui, Masato

AU - Kogner, P.

AU - Johnsen, J. I.

AU - Andäng, M.

AU - Uhlén, P.

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