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Reduced expression of beta-subunit of Na,K-ATPase in human clear-cell renal cell carcinoma
S A Rajasekaran1, W J Ball, N H Bander
1Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles 90095, USA.
Purpose:
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 a-subunit and a glycosylated beta-subunit whose function is still not well-defined.
Materials And Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Clear-cell renal cell carcinoma (RCC) shows significantly reduced beta-subunit levels of Na,K-ATPase, impacting kidney function. This diminished Na,K-ATPase activity is linked to the aggressive RCC tumor phenotype.
Area of Science:
- Nephrology
- Oncology
- Molecular Biology
Background:
- Clear-cell renal cell carcinoma (RCC) is an aggressive kidney cancer subtype.
- Na,K-ATPase is a vital kidney enzyme composed of alpha and beta subunits.
- The specific role of the Na,K-ATPase beta-subunit in kidney function and cancer remains unclear.
Purpose of the Study:
- To investigate the expression and activity of Na,K-ATPase subunits in clear-cell RCC.
- To determine the correlation between Na,K-ATPase levels and the clear-cell RCC phenotype.
Main Methods:
- Immunoblot analysis to quantify Na,K-ATPase alpha and beta-subunit protein levels in normal kidney and RCC tissues.
- Immunofluorescence and confocal microscopy to assess subunit localization.
- Spectrophotometric assay to measure Na,K-ATPase activity.
Main Results:
- Clear-cell RCC tissues exhibited a significant reduction (95.6%) in Na,K-ATPase beta-subunit levels compared to normal kidney.
- The alpha-subunit levels were generally maintained or increased in RCC.
- Reduced beta-subunit expression correlated with decreased Na,K-ATPase activity and loss of epithelial morphology in RCC.
Conclusions:
- The Na,K-ATPase beta-subunit may play a regulatory role in enzyme activity in vivo.
- Diminished Na,K-ATPase activity, associated with reduced beta-subunit levels, is linked to the clear-cell RCC phenotype.
- These findings highlight a potential mechanism underlying RCC development and progression.
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