Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy

Abstract

Lung cancer is a leading cause of global cancer deaths. Na/K-ATPase has been studied as a target for cancer treatment. Cardiotonic steroids (CS) trigger intracellular signalling upon binding to Na/K-ATPase. Normal lung and tumour cells frequently express different pump isoforms. Thus, Na/K-ATPase is a powerful target for lung cancer treatment. Drugs targeting Na/K-ATPase may induce apoptosis and autophagy in transformed cells. We argue that Na/K-ATPase has a role as a potential target in chemotherapy in lung cancer treatment. We discuss the effects of Na/K-ATPase ligands and molecular pathways inducing deleterious effects on lung cancer cells, especially those leading to apoptosis and autophagy.

The Na+/K+ATPase Regulates Glycolysis and Modifies Immune Metabolism in Tumors

“…Cardiac glycosides have been shown to exhibit antineoplastic effects in numerous settings 20,21,35 , which have been attributed to a myriad of sources such disruption of proton gradients 32 and activation of kinases that physically interact with the sodium-potassium pump (i.e. Na + /K + ATPase "signalosome") [62][63][64] . However, fluctuations in energetic demand from membrane transport activity have been shown to impact glycolytic rate 65 , and it has been historically hypothesized that alterations in Na + /K + ATPase activity may be a contributing factor to enhanced dependence on glycolysis in cancer 23 .…”

Anticancer and Immunogenic Properties of Cardiac Glycosides

“…In addition to identifying the primary target, multiple signaling pathways that are potentially activated or inhibited by CGs have been evaluated. From previous studies, some targets have been proposed, including ionic disturbances and changes in intracellular levels of Na + and K + ions, which can generate harmful effects and alter the conformation of many proteins [ 2 , 40 ]; inhibition of DNA topoisomerase II [ 41 ]; inhibition of the nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated pathways, which are constitutively active in many types of cancer [ 28 , 42 ]; changes in cell cycle, specifically blocking S and G2/M phases [ 43 , 44 ]; inhibition of interleukin (Il)-8 production [ 45 ]; and modulation of the myeloid cell leukemia-1 (Mcl-1) as an essential factor for cell death [ 2 , 28 , 46 ].…”

“…The effects of CGs on the ion exchange by the Na + /K + -ATPase have been investigated extensively. However, over the last 10 years, several studies determined that cells provide normal survival signals [ 30 , 40 , 51 ] and signs of death in tumor cells [ 52 ] when CGs bind to Na + /K + -ATPase. To explain this fact, the presence of two types of Na + /K + channels in the membrane was suggested [ 51 ].…”

Influence of Endogenous Cardiac Glycosides, Digoxin, and Marinobufagenin in the Physiology of Epithelial Cells

“…Some CG, including ouabain, digoxin, and digitonin, have been used as cardiac inotropic agents for almost 200 years; however, due to their narrow therapeutic index, the CG have been gradually replaced by other medications and presently are almost discontinued for this purpose [8]. Nonetheless, a fact that has given a renewed interest, on the study of these compounds, is the finding that apart from their effect on heart and hypertension, they influence an interesting variety of physiological and pathological processes, such as cell adhesion [9], growth, apoptosis, motility, and differentiation [10][11][12]. Among these, the ability to induce impairment of cell proliferation or activation of cell death by apoptosis or autophagy has led to consider CG as promising new therapeutic tools against cancer [13][14][15][16].…”