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Cited by 208Ion Transport and Channel RegulationProtein Kinase Regulation and GTPase SignalingDrug Transport and Resistance Mechanisms

Digitalis-Induced Signaling by Na+/K+-ATPase in Human Breast Cancer Cells

Kometiani, Peter, Liu, Lijun, Askari, Amir·2005·Molecular Pharmacology
DOI 10.1124/mol.104.007302
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Abstract

Because beneficial effects of digitalis treatment in breast cancer patients have been suggested by epidemiological studies, we explored the mechanism of the growth inhibitory effects of these drugs on the estrogen receptor-negative human breast cancer cell line MDA-MB-435 s. Ouabain concentrations (100 nM or lower) that caused less than 25% inhibition of the pumping function of Na+/K+-ATPase had no effect on cell viability but inhibited proliferation. At the same concentrations, ouabain 1) activated Src kinase and stimulated the interaction of Src and Na+/K+-ATPase with epidermal growth factor receptor (EGFR); 2) caused a transient and then a sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2); 3) increased the expression of p21Cip1 but decreased that of p53; and 4) activated c-Jun NH2-terminal kinase (JNK) but not p38 kinase. These data, in conjunction with our previous findings on the signaling role of Na+/K+-ATPase in other cells, suggest that ouabain-induced activation/transactivation of Src/EGFR by Na+/K+-ATPase leads to activation of ERK1/2, the resulting increase in the level of cell cycle inhibitor p21Cip1, and growth arrest. Cooperation of JNK with ERK1/2 in this process is also suggested. Digoxin and digitoxin concentrations close to or at the therapeutic plasma levels had effects on proliferation and ERK1/2 similar to those of ouabain, supporting the proposed potential value of digitalis drugs for the treatment of breast cancer.

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Crossref · 10.1124/mol.104.007302

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  • Digitalis, a sodium-potassium ATPase inhibitor, has been shown to limit the proliferation of human breast cancer cells.

    “For example, digitalis, a sodium-potassium ATPase inhibitor, has been shown to limit the proliferation of human breast cancer cells [72].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [72]

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Authors
Kometiani, P., Liu, L., & Askari, A.
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2005-03
Volume
67
Issue
3
Pages
929-936
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.104.007302
OpenAlex
W2136985880
Cited by
208
References
42
Citations by year
2026: 1 · 2025: 5 · 2023: 10 · 2022: 4 · 2021: 11 · 2020: 7 · 2019: 8 · 2018: 13 · 2017: 12 · 2016: 12 · 2015: 14 · 2014: 11 · 2013: 11 · 2012: 13
FWCI
3.43
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL-36573, P01HL036573)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
digitalis, ouabain, Na+/K+-ATPase, breast cancer, MDA-MB-435 cells, Src kinase, epidermal growth factor receptor, ERK1/2, JNK, p21, p53, cell proliferation inhibition, digoxin, digitoxin, growth arrest
MeSH terms
Sodium-Potassium-Exchanging ATPase, Breast Neoplasms, Cell Division, Cell Survival, Digitalis Glycosides, Female, Humans, Kinetics, Ouabain, Signal Transduction, Transcriptional Activation, Mitogen-Activated Protein Kinase 1, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3, ErbB Receptors

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