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

• Published in: PloS one 2015-04, Vol.10 (4), p.e0122442
• Main Authors: Huynh, Thu P, Barwe, Sonali P, Lee, Seung J, McSpadden, Ryan, Franco, Omar E, Hayward, Simon W, Damoiseaux, Robert, Grubbs, Stephen S, Petrelli, Nicholas J, Rajasekaran, Ayyappan K
• Format: Article
• Language: English
• Subjects: Adhesion; Animals; ATPases; Cancer; Cancer therapies; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - enzymology; Carcinoma, Renal Cell - pathology; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell adhesion molecules; Cell cycle; Cell Line, Tumor; Cell surface; Complications and side effects; Development and progression; Dexamethasone; Dexamethasone - pharmacology; Disease Progression; Drug development; Enzymes; Fluorometholone - pharmacology; Genetic aspects; Glucocorticoids; Glucocorticoids - pharmacology; Health aspects; HeLa Cells; High-throughput screening; High-Throughput Screening Assays; Humans; Invasiveness; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - enzymology; Kidney Neoplasms - pathology; Kinases; Laboratories; Male; Medical research; Mesenchyme; Metastases; Mice; Mice, Hairless; Mice, SCID; Motility; Na+/K+-exchanging ATPase; Neoplasm Invasiveness - prevention & control; Nephrectomy; Patient outcomes; Patients; Promoter Regions, Genetic - drug effects; Renal cell carcinoma; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Sodium-Potassium-Exchanging ATPase - genetics; Sodium-Potassium-Exchanging ATPase - metabolism; Steroid hormones; Steroids; Triamcinolone - pharmacology; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0122442

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.