Document Detail


Changes in sodium pump expression dictate the effects of ouabain on cell growth.
MedLine Citation:
PMID:  19329430     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Here we show that ouabain-induced cell growth regulation is intrinsically coupled to changes in the cellular amount of Na/K-ATPase via the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Ouabain increases the endocytosis and degradation of Na/K-ATPase in LLC-PK1, human breast (BT20), and prostate (DU145) cancer cells. However, ouabain stimulates the PI3K/Akt/mTOR pathway and consequently up-regulates the expression of Na/K-ATPase in LLC-PK1 but not BT20 and DU145 cells. This up-regulation is sufficient to replete the plasma membrane pool of Na/K-ATPase and to stimulate cell proliferation in LLC-PK1 cells. On the other hand, ouabain causes a gradual depletion of Na/K-ATPase and an increased expression of cell cycle inhibitor p21(cip), which consequently inhibits cell proliferation in BT20 and DU145 cells. Consistently, we observe that small interfering RNA-mediated knockdown of Na/K-ATPase is sufficient to induce the expression of p21(cip) and slow the proliferation of LLC-PK1 cells. Moreover, this knockdown converts the growth stimulatory effect of ouabain to growth inhibition in LLC-PK1 cells. Mechanistically, both Src and caveolin-1 are required for ouabain-induced activation of Akt and up-regulation of Na/K-ATPase. Furthermore, inhibition of the PI3K/Akt/mTOR pathway by rapamycin completely blocks ouabain-induced expression of Na/K-ATPase and converts ouabain-induced growth stimulation to growth inhibition in LLC-PK1 cells. Taken together, we conclude that changes in the expression of Na/K-ATPase dictate the growth regulatory effects of ouabain on cells.
Authors:
Jiang Tian; Xin Li; Man Liang; Lijun Liu; Joe X Xie; Qiqi Ye; Peter Kometiani; Manoranjani Tillekeratne; Runming Jin; Zijian Xie
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-03-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-25     Completed Date:  2009-06-29     Revised Date:  2013-06-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14921-9     Citation Subset:  IM    
Affiliation:
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Caveolin 1 / metabolism
Cell Line
Cell Proliferation / drug effects
Endocytosis / drug effects
Enzyme Activation / drug effects
Gene Expression Regulation, Enzymologic* / drug effects
Gene Knockdown Techniques
Humans
Organ Specificity / drug effects
Ouabain / pharmacology*
Phosphatidylinositol 3-Kinases / metabolism
Protein Kinases / metabolism
Protein Processing, Post-Translational / drug effects
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / genetics,  metabolism
Rats
Sirolimus / pharmacology
Sodium-Potassium-Exchanging ATPase / genetics,  metabolism*
Sus scrofa
TOR Serine-Threonine Kinases
src-Family Kinases / metabolism
Grant Support
ID/Acronym/Agency:
GM 78565/GM/NIGMS NIH HHS; HL-36573/HL/NHLBI NIH HHS; HL-67963/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Caveolin 1; 0/RNA, Messenger; 53123-88-9/Sirolimus; 630-60-4/Ouabain; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.10.2/src-Family Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.6.3.9/Sodium-Potassium-Exchanging ATPase
Comments/Corrections

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