REDUCED EXPRESSION OF beta-SUBUNIT OF NA,K-ATPASE IN HUMAN CLEAR-CELL RENAL CELL CARCINOMA

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Abstract
Multiple subtypes of renal cancer have been identified. Clear-cell renal cell carcinoma (RCC) is the most common subtype of RCC and one of the more aggressive. The goal of this study was to investigate in RCC the levels of Na,K-ATPase, an abundant enzyme in the kidney which is crucial for various kidney functions. Na,K-ATPase is a heterodimer consisting of a catalytic alpha-subunit and a glycosylated beta-subunit whose function is still not well-defined. Fourteen clear-cell RCC specimens were studied. The levels of the Na,K-ATPase alpha and beta-subunits in normal kidney and RCC tissues were determined by immunoblot analysis. The localization of the alpha and beta-subunits was studied by immunofluorescence and laser scanning confocal microscopy. Na,K-ATPase activity was determined using a coupled-enzyme spectrophotometric assay. In normal kidney, the cells demonstrate an epithelial morphology with distinct basolateral plasma membrane localization of the alpha and beta-subunits. Conversely, the cells of the clear-cell RCC have lost their epithelial phenotype and the alpha and beta-subunits show a diffuse intracellular staining. Clear-cell RCC tumor cell lysates showed a consistent 95.6 +/- 2.8% (mean +/- SD) reduction in protein levels of beta-subunit relative to the levels in normal kidney. The alpha-subunit level in RCC lysates was generally near or above the levels relative to normal kidney. The reduced beta-subunit expression was accompanied by a significant reduction in the Na,K-ATPase activity in RCC membranes. These results suggest that the beta-subunit may regulate the Na,K-ATPase activity in vivo. Diminished Na,K-ATPase activity in conjunction with the reduced beta-subunit level is associated with the clear-cell RCC phenotype.