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 (10μM)-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.