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

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-?1) 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-?1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-?1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-?1 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-?1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-?1. 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-?1 cell-cell adhesion function.

SUBMITTER: Huynh TP 

PROVIDER: S-EPMC4383530 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature