Evidence for a potential tumor suppressor role for the Na,K-ATPase ß₁-subunit

The Na,K-ATPase, consisting of two essential subunits (a, ß), plays a critical role in the regulation of ion homeostasis in mammalian cells. Recent studies indicate that reduced expression of the ß₁ isoform (NaK-ß₁) is commonly observed in carcinoma and is associated with events involved in cancer progression. In this study, we present evidence that repletion of NaK-ß₁ in Moloney sarcoma virustransformed Madin-Darby canine kidney cells (MSVMDCK), a highly tumorigenic cell line, inhibits anchorage independent growth and suppresses tumor formation in immunocompromised mice. Additionally, using an in vitro cell-cell aggregation assay, we showed that cell aggregates of NaK-ß₁ subunit expressing MSVMDCK cells have reduced extracellular regulated kinase (ERK) 1/2 activity compared with parental MSV-MDCK cells. Finally, using immunohistochemistry and fully quantitative image analysis approaches, we showed that the levels of phosphorylated ERK 1/2 are inversely correlated to the NaK-ß₁ levels in the tumors. These findings reveal for the first time that NaK-ß₁ has a potential tumor-suppressor function in epithelial cells.