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Cited by 104Cell death mechanisms and regulationIon Transport and Channel RegulationCancer Cells and Metastasis

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation

Simpson, Craig D., Mawji, Imtiaz A., Anyiwe, Kika, Williams, Moyo A., Wang, Xiaoming, Venugopal, Amudha L., Gronda, Marcela, Hurren, Rose, Cheng, Sonia, Serra, Stefano, Zavareh, Reza Beheshti, Datti, Alessandro, Wrana, Jeffrey L., Ezzat, Shereen, Schimmer, Aaron D.·2009·Cancer Research
DOI 10.1158/0008-5472.can-08-2530

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Abstract

Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed “anoikis.” However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na+/K+ ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na+/K+ ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides. [Cancer Res 2009;69(7):2739–47]

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Metadata

Authors
Simpson, C. D., Mawji, I. A., Anyiwe, K., Williams, M. A., Wang, X., Venugopal, A. L., Gronda, M., Hurren, R., Cheng, S., Serra, S., Zavareh, R. B., Datti, A., Wrana, J. L., Ezzat, S., & Schimmer, A. D.
Affiliations
  • Princess Margaret Cancer Centre (CA)
  • University Health Network (CA)
  • Mount Sinai Hospital (US)
  • University of Toronto (CA)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2009-04-01
Volume
69
Issue
7
Pages
2739-2747
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-08-2530
OpenAlex
W2097293117
Cited by
104
References
49
Citations by year
2026: 2 · 2025: 6 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 5 · 2016: 1 · 2015: 9 · 2014: 8 · 2013: 8 · 2012: 8
FWCI
4.16
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
anoikis, Na+/K+-ATPase inhibition, cardiac glycosides, ouabain, digoxin, digitoxin, strophanthidin, hypoosmotic stress, anchorage-independent survival, metastasis, prostate adenocarcinoma, natural products
MeSH terms
Sodium-Potassium-Exchanging ATPase, Animals, Cardiac Glycosides, Drug Screening Assays, Antitumor, Enzyme Activation, Enzyme Inhibitors, Humans, Male, Mitochondria, Neoplasm Metastasis, Neoplasms, Osmotic Pressure, Ouabain, Mice, SCID, Mice, Inbred NOD, Caspases, Xenograft Model Antitumor Assays, Anoikis, Cell Line, Tumor, Mice, Caspase Inhibitors

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