Regulation and pharmacological blockade of sodium-potassium ATPase: A novel pathway to neuropathy

Paúl, Dennis; Soignier, R. Denis; Minor, Lerna D.; Tau, Hui; Songu-Mize, Emel; Gould, Harry J.

doi:10.1016/j.jns.2014.03.012

Cited by 18 publications

(16 citation statements)

References 24 publications

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“…Serving as a multifunctional integrator and signal transducer, Na, K-ATPase is responsible for maintaining resting potential and regulating cellular volume, contractility, inflammation, adhesion and apoptosis [ 63 , 64 ]. The aberrant activity and expression of Na, K-ATPase have been implied in the progression of several types of aggressive cancers.…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibition Contributed to the Cytotoxicity of Arenobufagin after Its Binding with Na, K-ATPase in Human Cervical Carcinoma HeLa Cells

et al. 2016

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Although the possibility of developing cardiac steroids/cardiac glycosides as novel cancer therapeutic agents has been recognized, the mechanism of their anticancer activity is still not clear enough. Toad venom extract containing bufadienolides, which belong to cardiac steroids, has actually long been used as traditional Chinese medicine in clinic for cancer therapy in China. The cytotoxicity of arenobufagin, a bufadienolide isolated from toad venom, on human cervical carcinoma HeLa cells was checked. And, the protein expression profile of control HeLa cells and HeLa cells treated with arenobufagin for 48 h was analyzed using two-dimensional electrophoresis, respectively. Differently expressed proteins in HeLa cells treated with arenobufagin were identified and the pathways related to these proteins were mapped from KEGG database. Computational molecular docking was performed to verify the binding of arenobufagin and Na, K-ATPase. The effects of arenobufagin on Na, K-ATPase activity and proteasome activity of HeLa cells were checked. The protein-protein interaction network between Na, K-ATPase and proteasome was constructed and the expression of possible intermediate proteins ataxin-1 and translationally-controlled tumor protein in HeLa cells treated with arenobufagin was then checked. Arenobufagin induced apoptosis and G2/M cell cycle arrest in HeLa cells. The cytotoxic effect of arenobufagin was associated with 25 differently expressed proteins including proteasome-related proteins, calcium ion binding-related proteins, oxidative stress-related proteins, metabolism-related enzymes and others. The results of computational molecular docking revealed that arenobufagin was bound in the cavity formed by the transmembrane alpha subunits of Na, K-ATPase, which blocked the pathway of extracellular Na+/K+ cation exchange and inhibited the function of ion exchange. Arenobufagin inhibited the activity of Na, K-ATPase and proteasome, decreased the expression of Na, K-ATPase α1 and α3 subunits and increased the expression of WEE1 in HeLa cells. Antibodies against Na, K-ATPase α1 and α3 subunits alone or combinated with arenobufagin also inhibited the activity of proteasome. Furthermore, the expression of the possible intermediate proteins ataxin-1 and translationally-controlled tumor protein was increased in HeLa cells treated with arenobufagin by flow cytometry analysis, respectively. These results indicated that arenobufagin might directly bind with Na, K-ATPase α1 and α3 subunits and the inhibitive effect of arenobufagin on proteasomal activity of HeLa cells might be related to its binding with Na, K-ATPase.

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Section: Discussionmentioning

confidence: 99%

Proteasome Inhibition Contributed to the Cytotoxicity of Arenobufagin after Its Binding with Na, K-ATPase in Human Cervical Carcinoma HeLa Cells

et al. 2016

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“…In a model of systemic inflammation, male Sprague-Dawley rats that received an injection of Complete Freund’s adjuvant, which includes inactivated Mycobacterium tuberculosis , presented both α1- and α3-NKA isoform up-regulations, especially in primary afferent neurons, after 23 and 24 h ( 34 ). Furthermore, a recent study has brought some new insight as to how NKA may be involved in inflammatory processes in the somatosensory system ( 35 ).…”

Section: Importance Of Nka Subunits In Inflammation: a General Approamentioning

confidence: 99%

Cardiotonic Steroids as Modulators of Neuroinflammation

et al. 2016

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Cardiotonic steroids (CTS) are a class of specific ligands of the Na+, K+- ATPase (NKA). NKA is a P-type ATPase that is ubiquitously expressed and although well known to be responsible for the maintenance of the cell electrochemical gradient through active transport, NKA can also act as a signal transducer in the presence of CTS. Inflammation, in addition to importantly driving organism defense and survival mechanisms, can also modulate NKA activity and memory formation, as well as being relevant to many chronic illnesses, neurodegenerative diseases, and mood disorders. The aim of the current review is to highlight the recent advances as to the role of CTS and NKA in inflammatory process, with a particular focus in the central nervous system.

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“…Unfortunately, traditional methods for treating malignancy are fraught with serious morbidity and reduction in quality of life due to the toxic effects imposed on both normal and abnormal tissues. We propose a novel and promising approach for treating advanced and end-stage breast cancer that is based on coupling the observation that many of the most aggressive epithelially-derived carcinomas over-express voltage-gated sodium channels (VGSCs) [ 4 – 7 ], and the results of studies we have conducted on the role of VGSCs in the development and maintenance of chronic pain [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we observed that after the s.c. injection of complete Freund’s adjuvant (CFA), there is a rapid and dramatic increase in the expression of VGSC protein in the neurons associated with the area of robust and persistent inflammation that is produced [ 8 ]. We also observed a commensurate increase in sodium, potassium-ATPase (Na + , K + -ATPase or ‘sodium pump’) [ 11 ]. We have seen VGSC overproduction in excess of 50-fold, whereas the overproduction of sodium pumps has been 2- to 5-fold.…”

Section: Introductionmentioning

confidence: 99%

Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps

et al. 2018

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Sodium influx through voltage-gated sodium channels (VGSCs) coupled with balanced removal of sodium ions via Na+, K+-ATPase is a major determinant of cellular homeostasis and intracellular ionic concentration. Interestingly, many metastatic carcinomas express high levels of these channels. We hypothesized that if excess VGSCs are activated and Na+, K+-ATPase is simultaneously blocked, the intracellular Na+ concentration should increase, resulting in water movement into the cell, causing swelling and lytic cell death. MDA-MB-231 breast cancer cells over-express VGSCs by 7-fold. To test our hypothesis, we treated these cells in vitro with the Na+, K+-ATPase blocker, ouabain, and then stimulated with a sublethal electric current. For in vivo histologic and survival studies, MDA-MB-231 xenografts were established in Nu/J mice. Mice injected with saline or ouabain were electrically stimulated with trains of 10 msec 10V DC pulses. Within seconds to minutes, the cells swelled and lysed. MCF-10a cells, which express normal VGSCs levels, were unaffected by this treatment. Cells from the weakly-malignant cell line, MCF-7, which express 3-fold greater VGSCs than MCF-10a cells, displayed an intermediate time-to-lysis. The rate of lysis correlated directly with the degree of sodium channel expression and malignancy. We also demonstrated efficacy in cell lines from prostate, colon and lung carcinomas. Treated MDA-MB-231 xenografts showed 60–80% cell death. In survival studies, TOL-treated mice showed significantly slower tumor growth vs. controls. These results are evidence that this ”targeted osmotic lysis” represents a novel method for selectively killing cancer cells and warrants further investigation as a potential treatment for advanced and end-stage breast cancer.

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Regulation and pharmacological blockade of sodium-potassium ATPase: A novel pathway to neuropathy

Cited by 18 publications

References 24 publications

Proteasome Inhibition Contributed to the Cytotoxicity of Arenobufagin after Its Binding with Na, K-ATPase in Human Cervical Carcinoma HeLa Cells

Proteasome Inhibition Contributed to the Cytotoxicity of Arenobufagin after Its Binding with Na, K-ATPase in Human Cervical Carcinoma HeLa Cells

Cardiotonic Steroids as Modulators of Neuroinflammation

Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps

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