Abstract
Maintenance of Na+ and K+ gradients across the cell plasma membrane is an essential process for mammalian cell survival. An enzyme responsible for this process, sodium-potassium ATPase (NKA), has been currently extensively studied as a potential anticancer target, especially in lung cancer and glioblastoma. To date, many NKA inhibitors, mainly of natural origin from the family of cardiac steroids (CSs), have been reported and extensively studied. Interestingly, upon CS binding to NKA at nontoxic doses, the role of NKA as a receptor is activated and intracellular signaling is triggered, upon which cancer cell death occurs, which lies in the expression of different NKA isoforms than in healthy cells. Two major CSs, digoxin and digitoxin, originally used for the treatment of cardiac arrhythmias, are also being tested for another indication—cancer. Such drug repositioning has a big advantage in smoother approval processes. Besides this, novel CS derivatives with improved performance are being developed and evaluated in combination therapy. This article deals with the NKA structure, mechanism of action, activity modulation, and its most important inhibitors, some of which could serve not only as a powerful tool to combat cancer, but also help to decipher the so-far poorly understood NKA regulation.
Highlights
Cancer is a highly variable disease in terms of its origin and biological characteristics of the affected tissues
1 was able to cause SrcK inhibition in human cells derived from lung adenocarcinoma (A549), which led to downregulation of focal adhesion kinase (FAK), underlining the fact that interaction of cardiac steroids (CSs) with NKA in cancer cells leads to different outcomes than in non-transformed cells [116]
Showed that reactive oxygen species (ROS) induced a decrease in the NKA activity, which led to apoptosis of canine cancer cells, and this effect was abrogated by pretreatment with an antioxidant N-acetylcysteine
Summary
Cancer is a highly variable disease in terms of its origin and biological characteristics of the affected tissues. Targeting of NKA to the basolateral membrane is important because two adjacent cells are able to form tight junctions via β subunits interaction [34]. A significantly increased expression of the isoform 3 of the FXYD subunit was reported for hepatocellular [36], colorectal [37], urinary bladder [38], breast carcinoma [39], and pancreatic cancer [40]. The plots were prepared in R software, version 3.4.4 Another role of the FXYD subunit is to stabilize NKA in the cell plasma membrane via interaction with phosphatidylserine [60]. An individual isoform of the FXYD subunit modulates the NKA activity in dependence on an affinity for Na+ and K+ ions to NKA, see Another role of the FXYD subunit is to stabilize NKA in the cell plasma membrane via interaction with phosphatidylserine [60].
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