Glucocorticoids, including
dexamethasone (DEX) and
prednisone (
PRED), have been prescribed in patients with neoplastic disease as
cytotoxic agents or comedications. Nonetheless, it remains uncertain whether they have an impact on the development of
bladder cancer. We, therefore, assessed the functional role of the glucocorticoid-mediated
glucocorticoid receptor (GR) signaling in urothelial
tumorigenesis.
Tumor formation was significantly delayed in xenograft-bearing mice with implantation of control
bladder cancer UMUC3 cells or nonneoplastic urothelial SVHUC cells undergoing malignant transformation induced by a chemical
carcinogen 3-methylcholanthrene (MCA), compared with respective GR knockdown xenografts. Using the in vitro system with MCA-SVHUC cells, we screened 11 GR
ligands, including DEX, and found significant inhibitory effects of
PRED on their neoplastic transformation. The effects of
PRED were restored by a GR antagonist
RU486 in GR-positive MCA-SVHUC cells, while
PRED failed to inhibit the neoplastic transformation of GR knockdown cells. Significant decreases in the expression levels of oncogenes (c-Fos/c-Jun) and significant increases in those of a
tumor suppressor UGT1A were seen in MCA-SVHUC-control cells (vs GR-
short hairpin RNA) or
PRED-treated MCA-SVHUC-control cells (vs mock). In addition, N-butyl-N-(4-hydroxybutyl)
nitrosamine induced
bladder cancer in all of eight mock-treated mice vs seven (87.5%) of DEX-treated (P = .302) or four (50%) of
PRED-treated (P = .021) animals. Finally, DEX was found to considerably induce both transactivation (activation of
glucocorticoid-response element mediated transcription and expression of its targets) and transrepression (suppression of
nuclear factor-kappa B transactivation and expression of its regulated genes) of GR in SVHUC cells, while
PRED more selectively induced GR transrepression. These findings suggest that
PRED could prevent urothelial
tumorigenesis presumably via inducing GR transrepression.