In Vitro Study of the Multimodal Effect of Na+/K+ ATPase Blocker Ouabain on the Tumor Microenvironment and Malignant Cells
-
Published:2023-08-05
Issue:8
Volume:11
Page:2205
-
ISSN:2227-9059
-
Container-title:Biomedicines
-
language:en
-
Short-container-title:Biomedicines
Author:
Harich Octavia-Oana1, Gavriliuc Oana-Isabella1, Ordodi Valentin-Laurentiu12, Tirziu Alexandru1, Paunescu Virgil13, Panaitescu Carmen13ORCID, Bojin Maria-Florina13ORCID
Affiliation:
1. Department of Functional Sciences, Immuno-Physiology and Biotechnologies Center, “Victor Babes” University of Medicine and Pharmacy, No. 2 Eftimie Murgu Square, 300041 Timisoara, Romania 2. Faculty of Industrial Chemistry and Environmental Engineering, “Politehnica” University Timisoara, No 2 Victoriei Square, 300006 Timisoara, Romania 3. Center for Gene and Cellular Therapies in the Treatment of Cancer Timisoara-OncoGen, Clinical Emergency County Hospital “Pius Brinzeu” Timisoara, No. 156 Liviu Rebreanu, 300723 Timisoara, Romania
Abstract
Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes such as cell cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion, and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro to determine the effects of ouabain exposure on these cellular types. The results showed a multi-level effect of ouabain mainly on tumor cells, in a dose-dependent manner, while the TAFs and their normal counterparts were not significantly influenced. Following exposure to ouabain, the SK-BR-3 cells changed their morphologic appearance, decreased the expression of immunophenotypic markers (CD29, Her2, VEGF), the proliferation rate was significantly decreased (Ki67 index), the cells were blocked in the G0 phase of the cell cycle and suffered necrosis. These data were correlated with the variable expression of α and β Na+/K+ pump subunits in tumor cells, resulting in decreased ability to adhere to the VCAM-1 substrate in functional flow chamber studies. Being indicative of the pro-apoptotic and inhibitory effect of ouabain on tumor invasion and metastasis, the results support the addition of ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach.
Funder
Ministry of Investments and European Projects, Romania, project “Chimeric antigen receptor targeted oncoimmunotherapy with Natural Killer cells (CAR-NK)”
Subject
General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference44 articles.
1. Jung, J., Ryu, S., Ki, I.A., Woo, H.A., and Lee, K. (2018). Some Biological Consequences of the Inhibition of Na,K-ATPase by Translationally Controlled Tumor Protein (TCTP). Int. J. Mol. Sci., 19. 2. The translationally controlled tumour protein (TCTP);Bommer;Int. J. Biochem. Cell Biol.,2004 3. Hormonal regulation of Na+-K+-ATPase from the evolutionary perspective;Pirkmajer;Curr. Top. Membr.,2019 4. A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential;Botelho;Toxicon,2019 5. Kumavath, R., Paul, S., Pavithran, H., Paul, M.K., Ghosh, P., Barh, D., and Azevedo, V. (2021). Emergence of Cardiac Glycosides as Potential Drugs: Current and Future Scope for Cancer Therapeutics. Biomolecules, 11.
|
|