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

Kometiani, Peter; Liu, Lijun; Askari, Amir

doi:10.1124/mol.104.007302

Cited by 201 publications

(173 citation statements)

References 33 publications

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“…Previous reports as well as our current study (Figures 2a-c) suggest that the binding of ouabain or TCTP to the Na,K-ATPase a subunit stimulates Src-mediated EGFR phosphorylation, resulting in phosphorylation of other tyrosine residues on EGFR independent of serum (Haas et al, 2002;Kometiani et al, 2005;Kim et al, 2009). Phosphorylation of Tyr992 on EGFR has been reported to result in activation of PLC-g-mediated downstream signaling (Emlet et al, 1997) and phosphorylation of a pair of tyrosines 1148 and 1173, providing a docking site for scaffold proteins such as Shc, involved in the MAP kinase signaling pathway (Zwick et al, 1999).…”

Section: Discussionsupporting

confidence: 79%

“…For example, abnormal expression or activity of Na,K-ATPase, frequently observed in cancer cells, has been associated with tumor cell progression (Rajasekaran et al, 2001b;Espineda et al, 2003;Barwe et al, 2005). Conversely, inhibition of Na,K-ATPase by agents such as ouabain induces human cancer cell death (Haux, 1999;Kometiani et al, 2005). Nevertheless, the exact function of Na,K-ATPase in the molecular mechanisms underlying tumorigenesis is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

et al. 2011

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Translationally controlled tumor protein (TCTP) is implicated in cell growth and malignant transformation. TCTP has been found to interact directly with the third cytoplasmic domain of the a subunit of Na,K-ATPase, but whether this interaction has a role in tumorigenesis is unclear. In this study, we examined TCTP-induced tumor progression signaling networks in human breast epithelial cells, using adenoviral infection. We found that TCTP (a) induces Src release from Na,K-ATPase a subunit and Src activation; (b) phosphorylates tyrosine residues 845, 992, 1086, 1148 and 1173 on anti-epidermal growth factor receptor (EGFR); (c) activates PI3K (phosphatidylinositol 3-kinase )-AKT, Ras-Raf-MEK-ERK1/2, Rac-PAK1/ 2, MKK3/6-p38 and phospholipase C (PLC)-c pathways; (d) enhances NADPH oxidase-dependent reactive oxygen species (ROS) generation; (e) stimulates cytoskeletal remodeling and cell motility and (f) upregulates matrix metalloproteinase (MMP) 3 and 13. These findings suggest that TCTP induces tumorigenesis through distinct multicellular signaling pathways involving Src-dependent EGFR transactivation, ROS generation and MMP expression.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

et al. 2011

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“…9Ϫ11 Ouabain indeed inhibited Na ϩ /K ϩ -ATPase activity in HAECs as previously described in human arterial and venous endothelial cells. 11,26,27 Consistently, inhibition of Na ϩ /K ϩ -ATPase, via reduced extracellular potassium concentrations, blunted TNF-␣-induced endothelial TF expression. Ouabain has been described to inhibit gap junctions as well 18,28 ; however, an involvement of gap junctions in regulating TF expression can be ruled out, because the gap junction inhibitor carbenoxolone did not affect endothelial TF protein expression.…”

Section: Discussionmentioning

confidence: 77%

Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture

Stähli

Berndt

Akhmedov

et al. 2007

ATVB

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Background-Tissue factor (TF) plays an important role in acute coronary syndromes and stent thrombosis. This study investigates whether Na ϩ /K ϩ -ATPase regulates TF expression in human endothelial cells. Methods and Results-Ouabain inhibited tumor necrosis factor (TNF)-␣-induced endothelial TF protein expression; maximal inhibition occurred at 10 Ϫ5 mol/L, reached more than 70%, and was observed throughout the 5 hours stimulation period. The decrease in protein expression was paralleled by a reduced TF surface activity. Similarly, lowering of extracellular potassium concentration inhibited TNF-␣-induced TF protein expression. In contrast, ouabain did not affect TNF-␣-induced expression of full-length TF mRNA for up to 5 hours of stimulation; instead, expression of alternatively-spliced TF mRNA was upregulated after 3 and 5 hours of stimulation. Ouabain did not affect TNF-␣-induced activation of the MAP kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun terminal NH 2 kinase; activation of Akt and p70S6 kinase remained unaltered as well. Similar to the MAP kinases, ouabain did not affect TNF-␣-induced degradation of IB-␣. Ouabain had no effect on TF protein degradation. Conclusions-Naϩ /K ϩ -ATPase is required for protein translation of endothelial TF in culture. This observation provides novel insights into posttranscriptional regulation of TF expression. (Arterioscler Thromb Vasc Biol.

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“…Yet digitoxinmediated inhibition of the NF-B signaling pathway in cystic fibrosis lung epithelial cells has been demonstrated to be mechanistically distinct from Na ϩ ͞K ϩ -ATPase inhibition (23). With respect to other implicated cellular players, the nonlethal cardenolide concentrations that inhibit breast cancer cell proliferation also activate Src kinase, stimulate the interaction between Na ϩ ͞K ϩ -ATPase, the activated Src kinase, and epidermal growth factor (EGFR), and lead to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1͞2) and subsequent cell cycle arrest caused by increased levels of p21 Cip1 (35). Cardiac glycosides have also been demonstrated to initiate apoptosis via the classical caspase-dependent pathways in malignant T lymphoblasts (36) and prostate cancer cells (37).…”

Section: Resultsmentioning

confidence: 99%

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

Langenhan¹,

Peters²,

Guzei³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

218

174

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Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycosideinduced cytotoxicity and Na ؉ ͞K ؉ -ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.carbohydrate ͉ natural product ͉ sugar

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

Cited by 201 publications

References 33 publications

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

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

Cited by 201 publications

References 33 publications

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Translationally controlled tumor protein induces human breast epithelial cell transformation through the activation of Src

Cardiac Glycosides Regulate Endothelial Tissue Factor Expression in Culture

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

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Product

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