title: 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-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.
authors.affiliation: Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America; Nemours Center for Childhood Cancer Research, A. I. DuPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Thu P
authors.initials: TP
authors.lastname: Huynh
authors.affiliation: Nemours Center for Childhood Cancer Research, A. I. DuPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Barwe
authors.affiliation: Nemours Center for Childhood Cancer Research, A. I. DuPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Nemours Center for Childhood Cancer Research, A. I. DuPont Hospital for Children, Wilmington, Delaware, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: McSpadden
authors.affiliation: Department of Urologic Surgery, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Department of Urologic Surgery, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.affiliation: California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Grubbs
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Petrelli
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, Newark, Delaware, United States of America; Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America; Therapy Architects, 2700 Silverside Road, Wilmington, Delaware, United States of America.
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D018450:Disease Progression; D005469:Fluorometholone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D014221:Triamcinolone / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C503551:ATP1B1 protein, human; D005938:Glucocorticoids; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014221:Triamcinolone; D003907:Dexamethasone; D000254:Sodium-Potassium-Exchanging ATPase; D005469:Fluorometholone
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