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

Huynh TP, Barwe SP, Lee SJ, McSpadden R, Franco OE, Hayward SW, Damoiseaux R, Grubbs SS, Petrelli NJ, Rajasekaran AK - PLoS ONE (2015)

Bottom Line: 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.Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

GCs are less effective on NaK-β1 knockdown cells.(A) Cells were pre-treated with DEX and cell aggregation was assessed. Phase contrast images were acquired to depict the extent of cell-aggregation. The extent of cell-cell aggregation was quantified at 1 hr post-shaking and DEX treated conditions were expressed as a fold of DMSO treated samples. Asterisk indicates p-value was < 0.05. (B) Transwell invasion assay showing the relative invasiveness of Caki-1 and shRNA-β cells in the presence or absence of DEX pre-treatment. The invasion exhibited by DMSO was considered 100% for each cell line. The graph represents the mean±SE from three independent experiments (p-value < 0.05).
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pone.0122442.g007: GCs are less effective on NaK-β1 knockdown cells.(A) Cells were pre-treated with DEX and cell aggregation was assessed. Phase contrast images were acquired to depict the extent of cell-aggregation. The extent of cell-cell aggregation was quantified at 1 hr post-shaking and DEX treated conditions were expressed as a fold of DMSO treated samples. Asterisk indicates p-value was < 0.05. (B) Transwell invasion assay showing the relative invasiveness of Caki-1 and shRNA-β cells in the presence or absence of DEX pre-treatment. The invasion exhibited by DMSO was considered 100% for each cell line. The graph represents the mean±SE from three independent experiments (p-value < 0.05).

Mentions: A cell-cell aggregation assay revealed that DEX-treated Caki-1 cells produced larger cell aggregates compared to vehicle-treated cells. The shRNA-β knockdown cells were mostly mono-dispersed with occasional clusters at 2 hr (Fig 7A). DEX did not induce aggregation in either clone of shRNA-β cells (Fig 7A).


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

Huynh TP, Barwe SP, Lee SJ, McSpadden R, Franco OE, Hayward SW, Damoiseaux R, Grubbs SS, Petrelli NJ, Rajasekaran AK - PLoS ONE (2015)

GCs are less effective on NaK-β1 knockdown cells.(A) Cells were pre-treated with DEX and cell aggregation was assessed. Phase contrast images were acquired to depict the extent of cell-aggregation. The extent of cell-cell aggregation was quantified at 1 hr post-shaking and DEX treated conditions were expressed as a fold of DMSO treated samples. Asterisk indicates p-value was < 0.05. (B) Transwell invasion assay showing the relative invasiveness of Caki-1 and shRNA-β cells in the presence or absence of DEX pre-treatment. The invasion exhibited by DMSO was considered 100% for each cell line. The graph represents the mean±SE from three independent experiments (p-value < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383530&req=5

pone.0122442.g007: GCs are less effective on NaK-β1 knockdown cells.(A) Cells were pre-treated with DEX and cell aggregation was assessed. Phase contrast images were acquired to depict the extent of cell-aggregation. The extent of cell-cell aggregation was quantified at 1 hr post-shaking and DEX treated conditions were expressed as a fold of DMSO treated samples. Asterisk indicates p-value was < 0.05. (B) Transwell invasion assay showing the relative invasiveness of Caki-1 and shRNA-β cells in the presence or absence of DEX pre-treatment. The invasion exhibited by DMSO was considered 100% for each cell line. The graph represents the mean±SE from three independent experiments (p-value < 0.05).
Mentions: A cell-cell aggregation assay revealed that DEX-treated Caki-1 cells produced larger cell aggregates compared to vehicle-treated cells. The shRNA-β knockdown cells were mostly mono-dispersed with occasional clusters at 2 hr (Fig 7A). DEX did not induce aggregation in either clone of shRNA-β cells (Fig 7A).

Bottom Line: 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.Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus