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Glucocorticoids Suppress Renal Cell Carcinoma Progression by Enhancing Na,K-ATPase beta-1 Subunit Expression

Glucocorticoids Suppress Renal Cell Carcinoma Progression by Enhancing Na,K-ATPase beta-1 Subunit Expression

Thu P Huynh, Sonali P Barwe, Seung J Lee, Ryan McSpadden, Omar E Franco, Simon W Hayward, Robert Damoiseaux, Stephen S Grubbs, Nicholas J Petrelli, Ayyappan K Rajasekaran

PLoS One. 2015 Apr 2;10(4):e0122442.

PMID: 25836370

Abstract:

Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-β1) is a cell-cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high-throughput screening to identify small molecules that could up-regulate NaK-β1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-β1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-β1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-β1 cell-cell adhesion function.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6870946	Fluorometholone Related Compound A		6870-94-6	Price

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