Abstract
Ouabain, a cardiac glycoside found in plants, is primarily used in the treatment of congestive heart failure and arrhythmia because of its ability to inhibit Na+/K+-ATPase pump. Recently ouabain has been shown to exert anticancer effects but the underlying mechanism is not clear. Here, we explored the molecular mechanism by which ouabain exerts anticancer effects in human lung adenocarcinoma. Employing proteomic techniques, we found 7 proteins downregulated by ouabain in A549 including p-ezrin, a protein associated with pulmonary cancer metastasis in a dose-dependent manner. In addition, when the relative phosphorylation levels of 39 intracellular proteins were compared between control and ouabain-treated A549 cells, p-Src (Y416) was also found to be downregulated by ouabain. Furthermore, western blot revealed the ouabain-mediated downregulation of p-FAK (Y925), p-paxillin (Y118), p130CAS, and Na+/K+-ATPase subunits that have been shown to be involved in the migration of cancer cells. The inhibitory effect of ouabain and Src inhibitor PP2 on the migration of A549 cells was confirmed by Boyden chamber assay. Anticancer effects of ouabain in A549 cells appear to be related to its ability to regulate and inactivate Src-to-ezrin signaling, and proteins involved in focal adhesion such as Src, FAK, and p130CAS axis are proposed here.
Highlights
Ouabain (Figure 1(a)) is a cardiac glycoside found in plants and is primarily used in the treatment of congestive heart failure and cardiac arrhythmia because it inhibits the Na+/K+ATPase pump leading to a sequence of events including increase in the level of calcium ions and cardiac contractile force
Most of the previous studies of proteomic profile changes resulting from ouabain treatment focused on Na+/K+-ATPase suppression and were conducted in vascular smooth muscle cells (VSMCs) or in the endothelial cells (ECs) in order to identify the proteins involved in ouabain-induced regulation of cell proliferation and apoptosis and vascular remodeling [5,6,7,8] but not the proteins involved in ouabain’s anticancer effects
In this context we conducted a proteomic analysis of human lung adenocarcinoma A549 cells, treated with ouabain to identify the proteins altered when ouabain exhibits its anticancer effects, and it is possibly responsible for its anticancer effects
Summary
Ouabain (Figure 1(a)) is a cardiac glycoside found in plants and is primarily used in the treatment of congestive heart failure and cardiac arrhythmia because it inhibits the Na+/K+ATPase pump leading to a sequence of events including increase in the level of calcium ions and cardiac contractile force. Most of the previous studies of proteomic profile changes resulting from ouabain treatment focused on Na+/K+-ATPase suppression and were conducted in vascular smooth muscle cells (VSMCs) or in the endothelial cells (ECs) in order to identify the proteins involved in ouabain-induced regulation of cell proliferation and apoptosis and vascular remodeling [5,6,7,8] but not the proteins involved in ouabain’s anticancer effects In this context we conducted a proteomic analysis of human lung adenocarcinoma A549 cells, treated with ouabain to identify the proteins altered when ouabain exhibits its anticancer effects, and it is possibly responsible for its anticancer effects
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