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PMID: 22531632 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

British journal of cancer ·Vol. 106 ·No. 11 ·2012-05-22 ·Pages 1807-15

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

Abstract

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. 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. 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. 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.

MeSH Terms
Animals Cell Line, Tumor Cell Proliferation/drug effects Comet Assay Female Flow Cytometry Histones/metabolism Humans Mice Mice, Nude Neuroblastoma/metabolism Ouabain/metabolism,pharmacology Real-Time Polymerase Chain Reaction Sodium-Potassium-Exchanging ATPase/metabolism Transplantation, Heterologous
Chemicals
H2AX protein, human Histones Ouabain Sodium-Potassium-Exchanging ATPase
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Hiyoshi H
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-17177, Sweden.
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
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
1532-1827
DOI
10.1038/bjc.2012.159
Published
2012-05-22
Epub
2012-00-24
Pages
1807-15
Language
English
Region
England
NLM ID
0370635
PMCID
PMC3364115
Subset
IM
Corrections
CommentIn
PMID: 23681184
CommentIn
PMID: 23681185
External Links
PubMed source DOI: 10.1038/bjc.2012.159 PMC Full Text View journal details
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