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.
Highlights
Understanding the molecular basis of cancer cells in response to biologically derived substances is considered an essential aid to discovering novel molecular targets for drug therapies
We have provided evidence indicating that ouabain sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated lung cancer cell apoptosis, and this finding suggests that ouabain may affect cancer cell biology [7]
The results indicate that concentrations of ouabain at endogenous levels (2–770 pM) caused neither toxic nor proliferative effects on these lung cancer cells (Fig. 1C)
Summary
Understanding the molecular basis of cancer cells in response to biologically derived substances is considered an essential aid to discovering novel molecular targets for drug therapies. Increased kinase activity of focal adhesion kinase (FAK), a key signaling pathway controlling cell motility, potentiates tumorigenesis and metastasis [9] Such alterations were found during the acquisition process of metastatic cancer cells [10,11]. Akt that is localized at the edge of moving cells interacts with actin-binding proteins and induces actin remodeling and the formation of membrane protrusions, facilitating cell motility [15]. This concept was confirmed by a study showing that the down-regulation of Akt using an antisense technique causes a dramatic inhibition of cancer cell invasion in vitro [17] and in vivo [18]. The expression level of Cdc was found to be up-regulated in many cancers including lung cancer [21,22], and Cdc induction was shown to enhance cancer migration [23]
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