Increase in ouabain-sensitive K+-ATPase activity in hepatocellular carcinoma by overexpression of Na+,K+-ATPase α3-isoform

Na+,K+-ATPase is a housekeeping pump in virtually all animal cells. Recently, cardiac glycosides that inhibit Na+,K+-ATPase have been reported to be candidate for novel anticancer drug. Here, we investigated clinical significance of Na+,K+-ATPase α1-isoform (α1NaK), α2-isoform (α2NaK) and α3-isoform (α3NaK) in hepatocellular carcinoma (HCC). Interestingly, the expression levels of α3NaK protein in HCC tissues were significantly higher than those in the accompanying non-tumor tissues, whereas no significant increases in expression of α1NaK and α2NaK proteins were observed in HCC compared to non-tumor tissues. The ouabain (10 μM)-sensitive K+-ATPase activities (Na+,K+-ATPase activities) in the membrane fraction from HCC tissue were significantly higher than those from non-tumor tissues. The Na+,K+-ATPase activity was positively and significantly correlated with the expression level of α3NaK. Apparent affinity for Na+ in the Na+,K+-ATPase activity in HCC tissues was significantly lower than that in non-tumor tissues, consistent with an elevated expression of α3NaK relative to α1NaK. Our results suggest that overexpression of α3NaK increases the Na+,K+-ATPase activity of HCC cells.