Role of glucocorticoid signaling in urothelial tumorigenesis: Inhibition by prednisone presumably through inducing glucocorticoid receptor transrepression

Abstract

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.

The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

“…Suppression of NF-κB transactivation thus represents an indirect mechanism of glucocorticoid action referred to as GR transrepression. As described above, GR transrepression induced by prednisone [50] and CpdA [52] is associated with the prevention of urothelial tumorigenesis.…”

“…Meanwhile, it has been documented that prolonged systemic use of glucocorticoids use was at an increased risk of developing bladder cancer [49], presumably due to associated immune suppression. Our recent studies using the in vitro transformation system described above demonstrated that GR knockdown in SVHUC cells resulted in the significant prevention of MCA-induced neoplastic transformation of urothelial cells [50]. More interestingly, of a total of 11 glucocorticoids screened including dexamethasone, only prednisone significantly inhibited the neoplastic transformation of urothelial cells.…”

Activation of Glucocorticoid Receptor Inhibits the Stem-Like Properties of Bladder Cancer via Inactivating the β-Catenin Pathway

“…Next, we tried to explore its comprehensive effects in the BCa patients, and found that the expression levels of GR were lower in bladder tumors compared with bladder non-neoplastic tissue and in high-grade/MI tumors compared with low-grade/NMI tumors (28). Finally, we compared the inhibitory effects of 11 GR ligands, and found that prednisone significantly suppressed their neoplastic transformation (29). Previous studies indicated that GR might be a tumor-suppressor gene in the BCa, but the internal cause has been unknown.…”

The prognostic role of steroid hormone receptor signaling pathways in urothelial carcinoma

“…A case-control study demonstrated that prolonged use of glucocorticoids was associated with an elevated incidence of bladder cancer (50), presumably via immunosuppression. By contrast, our recent study has revealed that a synthetic glucocorticoid prednisone prevents the malignant transformation of GR-positive urothelial cells, but not that of GR-negative cells (51). Prednisone and other natural or synthetic glucocorticoids, such as corticosterone and dexamethasone, have also shown to strongly inhibit bladder cancer cell invasion and metastasis via, for instance, inactivating NF-κB (52-54).…”

“…Apart from glucocorticoid-induced immunosuppression, glucocorticoid-mediated GR signals appear to have dual roles (i.e., inhibition of tumor development and progression versus promotion of cell proliferation) in urothelial cancer. Further studies have indicated that the action of glucocorticoids may be dependent on a balance between transactivation and transrepression of GR ( 51 , 54 , 55 ) that involve their therapeutic effects and associated adverse effects, respectively. In particular, transrepression appears to correlate with the function of GR as a tumor suppressor.…”