Glucocorticoids suppress renal cell carcinoma progression by enhancing Na,K-ATPase beta-1 subunit expression.

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

doi:10.1371/journal.pone.0122442

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.

Highlights

IntroductionRenal cell carcinoma (RCC) consists of three main histologic types: clear cell, papillary, and chromophobe [2]
Kidney cancer is among the most frequent cancers diagnosed [1]
More recently we showed that the NaK-β1 promoter is silenced by hyper methylation in Renal cell carcinoma (RCC) [20] like many other tumor suppressors [21]

Summary

Introduction

Renal cell carcinoma (RCC) consists of three main histologic types: clear cell, papillary, and chromophobe [2]. The functional Na,K-ATPase consists of α- and β-subunits. The Na,K-ATPase α-subunit (NaK-α) is responsible for the catalytic function of the enzyme. The Na,K-ATPase β-subunit (NaK-β) associates with NaK-α in the endoplasmic reticulum to protect it from degradation and ensures the correct assembly and insertion of the mature enzyme into the plasma membrane. An accessory γ–subunit belonging to the FXYD family of proteins exhibits tissue specific expression and modulates Na,K-ATPase enzyme activity [5]. Of the four α- and three β-subunit isoforms known, the α1-subunit (NaK-α1) and β1-subunit (NaK-β1) are prominently expressed in most tissues, in the kidney [6]

Methods

Results

Conclusion