Contrary Regulation of Bladder Cancer Cell Proliferation and Invasion by Dexamethasone-Mediated Glucocorticoid Receptor Signals

Abstract

In patients with advanced bladder cancer, glucocorticoids are frequently given to reduce acute toxicity, particularly hyperemesis, during chemotherapy, as well as to improve cachectic conditions. However, it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor pathway. Glucocorticoid receptor expression was first investigated in human bladder cancer lines and tissue microarrays. Then, the effects of dexamethasone on glucocorticoid receptor transcription, cell proliferation, apoptosis/cell cycle, and invasion were examined in bladder cancer lines. Finally, mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression. All the cell lines and tissues examined were found to express glucocorticoid receptor. Dexamethasone increased glucocorticoid receptor-mediated reporter activity and cell proliferation, and inhibited apoptosis in the presence or absence of cisplatin. In contrast, dexamethasone suppressed cell invasion, the expression of its related genes [MMP-2/MMP-9, interleukin (IL)-6, VEGF], and the activity of MMP-2/MMP-9, and also induced mesenchymal-to-epithelial transition. In addition, dexamethasone increased IkBa protein levels and cytosolic accumulation of NF-kB. In xenograft-bearing mice, dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites, suggestive of peritoneal dissemination of tumor cells, and actual metastasis. In all these assays, dexamethasone effects were abolished by a glucocorticoid receptor antagonist or glucocorticoid receptor knockdown via RNA interference. Thus, glucocorticoid receptor activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis. These results may provide a basis of developing improved chemotherapy regimens, including or excluding glucocorticoid receptor agonists/antagonists, for urothelial carcinoma.

Loss of GATA3 in bladder cancer promotes cell migration and invasion

“…To link the above findings to epithelial-to-mesenchymal transition (EMT) implicated in invasion and metastasis of urothelial carcinoma, 18,19 we assessed expression levels of epithelial and mesenchymal markers by western blotting. As shown in Figure 4C, silencing of GATA3 was associated with an increasing level of a mesenchymal marker N-cadherin and a decreasing level of an epithelial marker β-catenin.…”

“…18 Briefly, cells (1.5 × 10 5 ) in 100 μl of serum-free medium were added to the upper chamber of the transwell, while 600 μl of medium containing 10% FBS was added to the lower chamber. After incubation for 36 h at 37 °C in a CO 2 incubator, invaded cells were fixed, stained with 0.1% crystal violet, and counted under a light microscope.…”

Expression of steroid hormone receptors and its prognostic significance in urothelial carcinoma of the upper urinary tract

“…[6][7][8] We have demonstrated that glucocorticoids directly mediate GR activity in BC cells and strongly inhibit BC cell invasion and metastasis. It is noteworthy, however, that some natural or synthetic glucocorticoids, such as hydrocortisone and dexamethasone, contradictorily promote BC cell proliferation via inhibiting apoptosis particularly that induced by a chemotherapeutic drug cisplatin.…”

“…It is noteworthy, however, that some natural or synthetic glucocorticoids, such as hydrocortisone and dexamethasone, contradictorily promote BC cell proliferation via inhibiting apoptosis particularly that induced by a chemotherapeutic drug cisplatin. 6,7 adjacent or separate non-neoplastic urothelial tissue specimens. 9 However, there were only a few studies demonstrating the expression of steroid hormone receptors, such as AR [10][11][12] and ERb, 11 in UUTUCs.…”

Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

“…PIP 3 binds to the PH domain of Akt resulting in phosphorylation and activation, which increases cell survival, growth, and metabolism (2,3). Interestingly, glucocorticoids (GCs), which inhibit growth (4) and induce apoptosis in a variety of cells (5), have been shown to increase expression of PTEN in A549 human lung carcinoma cells (6). This suggests that one aspect of the anti-growth properties of GCs may be mediated through the up-regulation of PTEN.…”