Ouabain Suppresses the Migratory Behavior of Lung Cancer Cells

Abstract

The migratory capability of cancer cells is one of the most important hallmarks reflecting metastatic potential. Ouabain, an endogenous cardiac glycoside produced by the adrenal gland, has been previously reported to have anti-tumor activities; however, its role in the regulation of cancer cell migration remains unknown. The present study has revealed that treatment with ouabain at physiological concentrations is able to inhibit the migratory activities of human lung cancer H292 cells. The negative effects of ouabain were found to be mediated through the suppression of migration regulatory proteins, such as focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (Akt), and cell division cycle 42 (Cdc42). We found that the observed actions of ouabain were mediated via a reactive oxygen species (ROS)-dependent mechanism because the addition of ROS scavengers (N-acetylcysteine and glutathione) could reverse the effect of ouabain on cell migration. Furthermore, ouabain was shown to inhibit the spheroidal tumor growth and decrease the cancer cell adhesion to endothelial cells. However, the compound had no significant effect on anoikis of the cells. Together, these findings shed light on the understanding of cancer cell biology by exploring the novel function of this endogenous human substance.

Inhibition of cell proliferation, invasion and migration by the cardenolides digitoxigenin monodigitoxoside and convallatoxin in human lung cancer cell line

“…Nevertheless, p-FAK was also downregulated by CON and DGX. In line with these results, ouabain, another well-known cardiac glycoside, inhibited cancer cell migratory Downloaded by [RMIT University] at 00:46 11 August 2015 behavior by suppression of FAK activation (Pongrakhananon et al 2013) and decreased MMP-2 and MMP-9 expression ) on lung cancer cells.…”

“…Based on these findings, extensive experiments have been conducted to determine the action mechanism of cardenolides, demonstrating the ability of these compounds to inhibit cell growth, arrest cell cycle, and induce apoptosis and/or autophagy in different cancer cells (Juncker et al 2011;Wang et al 2012;Cerella et al 2013). Additionally, cardenolides such as ouabain have been reported to reduce the migration and invasive characteristics of some cancer cell lines (Pongrakhananon et al 2013). However, only a few studies have evaluated the migration and invasion potential of cardenolides by in vitro assays (Klausmeyer et al 2009;Pongrakhananon et al 2013;Yang et al 2014).…”

“…Additionally, cardenolides such as ouabain have been reported to reduce the migration and invasive characteristics of some cancer cell lines (Pongrakhananon et al 2013). However, only a few studies have evaluated the migration and invasion potential of cardenolides by in vitro assays (Klausmeyer et al 2009;Pongrakhananon et al 2013;Yang et al 2014). Thus, further studies are needed, to elucidate their metastatic potential.…”

Ouabain‐regulated phosphoproteome reveals molecular mechanisms for Na + , K + ‐ATPase control of cell adhesion, proliferation, and survival

“…demonstrated that ouabain, when employed at a subsaturating concentration, plays a major role in regulating the permeability and composition of tight junctions (8, 9, 43). Furthermore, cell adhesion molecules play a significant role in cancer progression and metastasis, and many of the adhesive molecules phosphorylated in response to ouabain have been suggested as potential therapeutic targets in cancer (44, 45). Our findings will offer further insights into the molecular mechanisms whereby ouabain regulates cell adhesion.…”

Plumbagin-induced oxidative stress leads to inhibition of Na+/K+-ATPase (NKA) in canine cancer cells

“…Therefore, there are initiatives to develop NKA inhibitors as chemotherapeutics for the treatment of cancer. A majority of these studies have focused on digoxin, ouabain and other cardiac glycosides because of their known ability to potently inhibit NKA activity [6][7][8][9][10][11].…”