ArticleThe Journal of biological chemistry2009
Changes in sodium pump expression dictate the effects of ouabain on cell growth.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 1 synthesis or guideline pooled it, 122 citations in OpenAlex.
- Digoxin use and risk of invasive breast cancer: evidence from the Nurses' Health Study and meta-analysis.Breast cancer research and treatment · 2014Pooled it
- Ouabain increases neuronal differentiation of hippocampal neural precursor cells.Current research in neurobiology · 2025Article
- Ouabain - a double-edged sword in tumor development and progression? a review of half a century.Frontiers in physiology · 2025Review
- Factors that influence the Na/K-ATPase signaling and function.Frontiers in pharmacology · 2025Review
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- Trop-2, NaOncogene · 2022Article
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- Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane CaJournal of cellular biochemistry · 2021Article
- FXYD2 mRNA expression represents a new independent factor that affects survival of glioma patients and predicts chemosensitivity of patients to temozolomide.BMC neurology · 2021Article
- Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics.Biomolecules · 2021Review
- The Na/K-ATPase α1/Src interaction regulates metabolic reserve and Western diet intolerance.Acta physiologica (Oxford, England) · 2021Article
- Biased Effect of Cardiotonic Steroids on Na/K-ATPase-Mediated Signal Transduction.Molecular pharmacology · 2021Article
- Inhibition of endogenous ouabain by atrial natriuretic peptide is a guanylyl cyclase independent effect.PloS one · 2021Article
- 21-Benzylidene digoxin decreases proliferation by inhibiting the EGFR/ERK signaling pathway and induces apoptosis in HeLa cells.Steroids · 2020Article
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- Article
- Ouabain Enhances Cell-Cell Adhesion Mediated by βInternational journal of molecular sciences · 2019Article
- Cardiotonic Steroids-A Possible Link Between High-Salt Diet and Organ Damage.International journal of molecular sciences · 2019Review
- Proliferation-related changes in KScientific reports · 2019Article
- The cardenolide ouabain suppresses coronaviral replication via augmenting a NaToxicology and applied pharmacology · 2018Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.